Pain is common and often poorly managed1,2. Globally, it has been estimated that 1 in 5 adults suffer from pain and that another 1 in 10 adults are diagnosed with chronic pain each year3. Apart from acute pain associated with surgery or tissue damage, approximately 28 million adults in the UK live with chronic pain 4,5. ). Indeed, between 10.4% and 14.3% of adults experience moderately to severely disabling chronic pain4. Pain can markedly undermine quality of life – affecting activities of daily living, employment and prognosis – dramatically increase use of health resources and is associated with increased mortality6–8. For instance, up to 84% of adults experience chronic low back pain, the second leading cause of disability worldwide and the most common musculoskeletal disease9. Indeed, 5 of the 11 conditions that impose the greatest global health burden are pain-related10.
Meet the experts
- Dr Dominic Aldington is Clinical Lead for Pain Management, Hampshire Hospitals NHS Trust, UK
- Maxime Dougados is Professor of Rheumatology at the René Descartes University – Paris and Cochin Hospital, Paris, France
- Ayman Ebied is Professor of Orthopaedics at Menoufia University Hospitals, Al Minufya, Egypt
- Professor Hartmut Göbel is Medical Director for Neurology and Behavioural Medicine in the Pain Clinic, Kiel, Germany
- Professor Marc Hochberg is Division Head, Rheumatology and Clinical Immunology at the University of Maryland School of Medicine, Baltimore, US.
- Professor Andrew Moore is Director of Pain Research, Nuffield Department of Anaesthetics at the University of Oxford, UK
- Professor Seza Özen is Head of the Department of Paediatric Rheumatology, Hacettepe University Faculty of Medicine in Ankara, Turkey
- Professor José Pereira da Silva is Head of the Rheumatology Department, University Hospital Coimbra, Portugal
- Dr Meeta Singh is a Gynaecologist and Obstetrician at Tanvir Hospital, Hyderabad, India
When evaluating and treating a patient presenting with pain, taking a comprehensive history and accurately assessing pain severity are essential. Determining patient comorbidities, such as cardiovascular and renal disease, depression and anxiety, along with factors such as age and pregnancy, will help inform treatment decisions and individualise therapy. There are a number of treatment options available for pain, including non-pharmacological approaches, non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol and opioids.
This section of the Learning Zone also includes videos on tension-type and migraine headaches and case studies of treating pain during:
- juvenile idiopathic arthritis (JIA)
- osteoarthritis (OA) in the elderly.
Measurement and assessment
How is pain measured and assessed?
In this video, Professor Moore reviews the interpretation of the visual analogue scale (VAS), which is widely used to assess pain severity.
Accurate assessment is the foundation of optimal pain management5. Nevertheless, because pain is highly subjective, assessing severity can be difficult. Indeed, healthcare professionals (HCPs) and patients often differ in their perception of pain severity associated with a condition or extent of tissue damage11.
A score of more than 30 mm on the VAS (Figure 1) suggests moderate pain12. Professor Moore argues that any outcome worse than mild pain is unacceptable and usually indicates analgesic or treatment failure13.
Pain is often poorly managed1,2. In this series of detailed case studies, leading clinicians discuss the challenges posed by optimising and individualising pain management throughout the patients’ life exemplified by: juvenile idiopathic arthritis; treating pain during pregnancy; and OA in the elderly. Individualising treatment also means being cognisant of the influence of comorbidities on patients’ experience and treatments. Depression and pain are mutually reinforcing, for example14. So, antidepressants can be part of the pain management programme for some patients15. Understanding NSAIDs’ mode of action on pain and the cardiovascular system can help individualise pain treatment16.
Managing pain in juvenile idiopathic arthritis
What is the right treatment for a paediatric patient with JIA?
In this case study, Professors Özen and Ebied discuss the management of Aleyna, a young girl with JIA.
Professor Özen notes that pain is the most common and distressing symptom of JIA and can persist despite adequate treatment of the inflammatory component17. As a result, age-appropriate pain treatment is essential, which includes managing arthritic inflammation, NSAIDs, physiotherapy and exercise.
Aleyna, for example, was able to exercise at school. Unfortunately, she fractured her tibia playing volleyball. Professor Ebied reviews the management of the fracture, which encompasses preventive and post-operative analgesia. Multimodal management of analgesia often proves successful for patients undergoing surgery for trauma. He also notes that NSAIDs are an important element in post-operative pain management and may be opioid sparing18.
Professors Özen and Ebied answer the following questions in the final part of the video:
- What are the best NSAID recommendations in JIA?
- Is there a role for NSAIDs in pre-operative pain control? If so, what would be your preferred NSAID?
- Can tramadol be used in JIA?
- How long can diclofenac be used in JIA?
- How do NSAIDs affect bone healing in JIA?
Treating pain during pregnancy
What is the most appropriate treatment for a patient with RA before, during and after pregnancy?
In this case study, Professor Pereira da Silva and Dr Singh discuss a 35-year-old secretary, who suffers from rheumatoid arthritis (RA) and wants to start a family.
Pain during pregnancy is common: up to 90% of pregnant women report low back pain, for example1.Pain during pregnancy can also arise from a worsening of a pre-existing condition, such as arthritis, headache or fibromyalgia1. However, management of chronic pain during pregnancy and while breastfeeding can prove challenging, partly because of uncertainties regarding analgesic safety in pregnancy and lactation on the mother and baby1. To complicate matters further, the marked anatomical and physiological changes that arise during pregnancy and that affect most organ systems potentially alter pharmacokinetics and pharmacodynamics. Nevertheless, few studies assess the clinical consequences of altered pharmacokinetics during pregnancy19. As a result, pain in pregnant women is often undertreated1.
The case history for this patient shows that management should aim at inducing RA remission and ensuring adequate pain control. As she wants to start a family, individualised and comprehensive preconception counselling is essential, that goes beyond the pharmacological management of RA and pain to encompass nutrition, emotional and social support, and implications for breast feeding.
Professor Pereira da Silva and Dr Singh answer the following questions in the final part of the video:
- Which of diclofenac or paracetamol is safe to use in a pregnant woman with RA?
- What NSAID is best used in seronegative RA and seropositive RA?
- Is there any role for immunomodulators?
- What is the ideal time interval between stopping of methotrexate and planning a pregnancy?
Pain management in osteoarthritis
What is the most appropriate treatment for an elderly patient with OA and ling-term lower back pain?
Professors Pereira da Silva and Ebied discuss a 65-year-old retired school teacher with knee OA.
Management of the pain associated with OA includes education, weight reduction, activity and analgesics. Alleviating pain in people with OA can improve productivity, quality of life and emotional well-being while reducing the impact on work productivity and reducing use of healthcare resources. Analgesics are an important element of multidisciplinary care. The choice of NSAIDs for chronic use by an elderly patient depends on several factors including their gastrointestinal, renal and cardiovascular risk, comorbidities and drug-drug interactions, such as with antihypertensives20,21.
Nevertheless, NSAIDs can be opioid sparing22,23. A Cochrane review noted that non-tramadol opioids produced a small mean improvement in pain and function in knee or hip OA compared with placebo. Opioids were, however, associated with significant increases in adverse events 24. Professor Pereira da Silva also reviews the SPACE study, which compared 12-months treatment with opioid and non-opioid analgesics in patients with moderate to severe chronic back pain or hip or knee OA. Opioid and non-opioid analgesics produced similar improvements in pain-related function. The improvement in pain intensity, however, was better in the non-opioid group. Adverse events were more common with opioids than non-opioids23.
Management of post-operative pain in older people raises additional concerns. Professor Ebied explains that pain management following primary knee arthroplasty requires a multimodal approach. For example, NSAIDs added to patient-controlled morphine analgesia offers some advantages compared with morphine alone for post-operative pain. NSAIDs are also opioid sparing following surgery22.
Professor Ebied answers the following questions in the final part of the video:
- Is there a role for cryoablation of the genicular nerves as a preoperative pain control method?
- Would you recommend neuromodulation of the sensory nerves in osteoarthritis of the knee?
- Is platelet-rich plasma effective for controlling pain in patients with OA?
Pain management in a patient with comorbidities
What is the most appropriate treatment for an elderly patient with OA along with hypertension and obesity?
In this video, Professor Hochberg discusses a 62-year-old woman with OA, mild hypertension and obesity.
Pain is often associated with psychological and physical comorbidities – including depression and anxiety, obesity as well as renal and cardiovascular disease – that may influence outcomes14,25,26. For example, obesity and chronic pain may negatively impact disability, quality of life, treatment responsiveness, satisfaction with care, healthcare use and cost more than either condition alone25.NSAIDs can produce cardiovascular side effects by, for example, increasing blood pressure (typically by 6 to 7 mmHg) and inducing peripheral oedema. NSAIDs can contribute to renal disease by promoting salt and water retention and through direct nephrotoxicity26
Professor Hochberg examines the mode of action of NSAIDs and how these pharmacological actions improve pain and functioning, while influencing the cardiovascular system (Figure 2)16.Understanding NSAIDs’ mode of action can help individualise treatment to the patient.
Pain, depression and anxiety
Is there a relationship between pain and depression?
Professor Pereira da Silva suggests that antidepressants can be part of the pain management programme for some patients.
Depression and anxiety are common comorbidities among people experiencing pain. For example, a meta-analysis of 49 studies suggested that 21.3% and 19.9% of patients with OA experience anxiety and depression, respectively. Compared with healthy controls, people with OA were 35% and 17% more likely to experience anxiety and depression, respectively14. Depression and pain can be mutually reinforcing. So, screening people with chronic disease, especially if painful, for depression and anxiety is important (Table 1).
Table 1. Questions to screen for depression and anxiety (Adapted from National Institute for Health and Care Excellence27).
Compared with placebo, for example, duloxetine significantly reduced pain and improved function in patients with knee OA: 44.1% and 65.3% of patients reported showed at least a 30% reduction in pain. On the other hand, significantly more patients in the duloxetine group (18.8%) discontinued treatment because of adverse events compared with placebo (5.5%)15
Based on the proportion of patients who report at least a 50% reduction in pain, duloxetine seems to be an effective analgesic for OA, fibromyalgia, chronic low back pain and diabetic peripheral neuropathic pain. Outcomes with duloxetine tend to be bimodal with patients experiencing either very good or very poor pain relief28.
Pain’s impact on quality of life
How is chronic pain defined and how does it impact quality of life?
In this video, Professor Dougados considers pain’s impact on quality of life and use of health resources.
Pain can have a major impact on activities of daily living, employment and prognosis 6,7. Indeed, chronic low back pain is the second leading cause of disability worldwide9Moreover, the severity of disability in people with OA in their hip or knee or both is associated with a significant increase in all-cause mortality and serious cardiovascular events after allowing for confounders6. . Partly because of these factors, healthcare costs are at least 2.6 times higher (Figure 3) in people with chronic pain compared with those without chronic pain or who experience mild pain7.
HCPs need to balance analgesic’s benefits against the risk of side effects. For example, in older people (mean age 80.0 years) opioids were associated with a 68% increased risk for safety events requiring hospitalisation compared with nonselective NSAIDs. Opioids were also associated with an 87% in the risk of all-cause mortality compared with nonselective NSAIDs8. Despite these concerns, inappropriate long-term opioid use is widespread despite poor efficacy for non-cancer pain, potential harm and being incompatible with best practice29. Against this background, Professor Dougados examines the implications of these factors for HCPs considering the optimal treatment.
Headache disorders are common: 66% of people worldwide experience headache disorders at some time30. About 46% of people worldwide experience tension-type headaches (TTH), 14% migraines and 3% chronic headaches, which last more than 15 days a month30. Headaches impose a heavy economic burden on society, predominately because of loss of work time, and on patients’ quality of life30The videos in this section explore the optimal management of TTH and migraines.
How effective are analgesics for treating tension type headache (TTH)?
In this video, Professor Moore and Dr Aldington discuss the main acute treatments for TTH, which include ibuprofen, ketoprofen and paracetamol.
In a year-long study, 86% of adults aged 25–36 years reported suffering TTH, the most common headache disorder31,32. People with TTH typically report a ‘band-like’ pain that radiates across both sides from the forehead to the back of the head. Many people report that the pain of TTH spreads to the neck muscles and patients describe the sensation as tightness, pressure or a dull ache33.
What analgesics are suitable for treating acute migraine?
In this video, Professor Göbel notes that about half of adults experience a headache disorder, such as tension-type headaches (TTH) or migraine), over a year (Figure 4).
In this video, Professor Göbel notes that about half of adults experience a headache disorder, such as tension-type headaches (TTH) or migraine), over a year (Figure 4).
Professor Göbel comments that the International Headache Society classification allows a precise diagnosis of migraine, which consists of several subtypes (available at ichd-3.org). When managing a migraine patient, he stresses the importance of addressing behavioural, nutritional and other trigger factors as well as considering the most appropriate pharmacological treatment and analgesic for each patient. The optimal strategy depends on tailoring the preventive drug based on headache frequency and severity, the degree of disability arising from the migraine and any comorbidities.
Ask the expert: headaches
In this Ask the Expert session, Professor Göbel takes an in-depth look at the nuances of diagnosing and managing headaches.
The question and answer session covers, among other topics, differential diagnosis of TTH, cluster headache and migraine, NSAIDs’ place in migraine management and the treatment of vomiting patients.
Specific questions answered include:
- Can nasal oxygen be used to differentiate between migraine and cluster headache?
- Is there any difference between NSAIDs for the treatment of migraine and non-migraine headache?
- Is there any role for opioids in any type of migraine?
- What are the major differences between tension-type and migraine headache?
- Do beta blockers cause hypotension in normotensive migraine patients?
- What are the circumstances in which you would seek a psychiatric evaluation for chronic headache?
Despite numerous analgesics and non-pharmacological treatments, pain is often poorly managed. Poor pain management is, in turn, associated with an increased risk of mortality2,34,35. This section of the Learning Zone considers, in more detail: non-pharmacological pain management; treatment of acute pain; the role of paracetamol and opioids; how HCPs can reduce the risk of gastrointestinal complications; and the importance of NSAID formulation.
What is the impact of pain in chronic conditions?
In this video, Professor Moore notes that five of the 11 conditions that impose the greatest global health burden in terms of years lived with disability are pain-related: back pain, neck pain, other musculoskeletal disease, migraine and OA10.
Despite being common, there is often a discrepancy between HCPs’ and patients’ perception of the pain associated with a particular condition, or level of tissue damage. In a study of 646 people with RA, differences in pain evaluation explained 34.6% of the discordance between physicians’ and patients’ global assessment of disease activity11.
Professor Moore added that pain is often poorly managed. A study of 1,187 people with knee osteoarthritis found that 54% reported an average pain score of more than 4 on a 10-point scale, the definition of inadequate pain relief2.
Making sense of risk in the treatment of pain
Should treatment decisions be based on absolute or relative risk?
Managing pain depends on balancing the risks and benefits of the different options as well as not offering adequate treatment. Analgesics, for example, are associated with side effects. But as Professors Moore and Pereira da Silva discuss with Dr Aldington, inadequate pain management also carries risks.
Patients and prescribers need to consider absolute and relative risks, possible sources of bias and potential confounders in the study, and comparative efficacy, which can be determined using network meta-analyses.
For example, a series of cohort studies reported a 50% and 70% increase in the rate of major adverse cardiovascular events (MACE) and cardiac death respectively in people taking diclofenac compared with no NSAID. However, the absolute increase for MACE increased from 4 per 10,000 people with no NSAID to between 7 and 11 per 10,000 with diclofenac. The absolute increase for cardiac death was 1 per 10,000 people from 1 to 2 per 10,000 with no NSAID and diclofenac respectively36.
On the other hand, inadequate pain management is associated with risks. One study followed 1,163 patients with hip or knee osteoarthritis (OA) for a median of 14 years. All-cause standardised mortality was 55% higher in patients with OA. Fifty-three per cent of people with walking disability at baseline died compared with 33% of controls, a 48% increase after allowing for confounders35. A study that enrolled 677 patients with ankylosing spondylitis found that work disability (odds ratio 3.65) and not using NSAIDs (OR 4.35) increased mortality around four-fold34.
What is the role of physical therapy in patient rehabilitation after injury?
In this question and answer session, Professor Moore and Dr Aldington discuss the importance of physiotherapy, exercise and other non-pharmacological treatments in the management of musculoskeletal pain.
Dr Aldington stresses the value of physiotherapy to improve balance in older people, who often lose confidence if they have a fall. The discussions also encompass the role of muscle relaxants and the role of paracetamol and combination treatments containing NSAIDs in the care of people with musculoskeletal pain.
Questions answered include:
- What about the use of muscle relaxants in chronic musculoskeletal pain?
- How important is physiotherapy in getting people back from a state of injury to full function?
- Is there any benefit of combining and NSAID and paracetamol for acute pain?
- Does the use of diclofenac slow bone healing?
Management of acute and chronic pain
What would be the most effective treatment for moderate-to-severe pain?
In this video, Dr Aldington defines acute pain and explains that fast-acting analgesic formulations tend to have the lowest number needed to treat (Figure 5).
Acute pain – which is associated with tissue damage and effects mood, rehabilitation and function – is common. In one study, 65% of patients in hospital reported experiencing pain in the previous 24 hours. Of these, 81% said that the pain was moderate or severe37. Paracetamol and aspirin are less effective than NSAIDs.
Ask the expert: Acute and chronic pain
In these Ask the Expert videos, Professors Hochberg, Pereira da Silva and Moore discuss factors to consider when optimising analgesia including the treatment duration, dose titration and renal tolerability for both chronic and acute pain.
Questions answered regarding chronic pain:
- How long can we continue using diclofenac in a patient?
- Are the dose-response relationships seen in the da Costa network meta analysis relevant to daily practice?
- Is there any new information on nephrotoxicity?
- What about the use of paracetamol together with an NSAID?
In the second part of the video, Professor Moore and Dr Aldington answer questions about the optimal management of acute post-operative pain:
- Can we use the NNT (number needed to treat) for clinical decision-making?
- Should NSAIDs be used continuously or only when pain is present?
- Should fixed dosing or PRN (as needed) be used in a hospital setting?
- Is injectable diclofenac the most widely used injectables for pain globally?
- Are there any studies comparing the efficacy of combinations of paracetamol and opioids with diclofenac
- Are there any pain markers available for screening?
- How long can we safely give analgesics for chronic back pain?
Efficacy and safety: Considerations for the elderly
Should gastroprotective agents be prescribed alongside NSAIDs in the elderly?
Professor Moore discusses the topic of increased gastrointestinal events with NSAID treatment.
NSAIDs increase the risk of gastrointestinal events, such as ulcers and gastrointestinal bleeds. NSAID-related gastrointestinal events can be more serious than those arising from other causes. A meta-analysis suggested that mortality in patients with an upper gastrointestinal bleed or perforation is 7.4% overall. Mortality is higher (20.9%) in people with an upper gastrointestinal bleed or perforation who are exposed to NSAID or aspirin39.
The increased risk of gastrointestinal events is particularly pronounced in the elderly. Professor Moore notes that gastroprotective agents, such as proton pump inhibitors (PPIs) and histamine receptor 2 antagonists (H2A), reduce the risk (Figure 6).
PPIs seem to be more effective than H2A at preventing NSAID-related gastrointestinal events: the numbers needed to treat to prevent one event are 4.7 and 7.7 respectively. Nevertheless, about half of patients with gastrointestinal risk factors taking NSAIDs are not prescribed adequate gastroprotection or any gastroprotective agent40.
The role of opioid analgesics
Are opioids suitable for all types of pain?
In this video, Professors Moore and Pereira da Silva discuss with Dr Aldington the efficacy and safety of opioids in several settings, including cancer pain, where robust evidence is surprisingly sparse, low back pain, OA, neuropathic pain and fibromyalgia, post-operative pain and renal colic pain.
Inappropriate long-term opioid use is common despite poor efficacy for non-cancer pain, potential harm and being incompatible with best practice29.
The panel review management of post-operative pain, noting that HCPs can use a variety of techniques (e.g. nerve block) and analgesics to alleviate patients’ discomfort. The literature, however, contains only small studies, which complicates attempts to optimise management of intra- and post-operative pain. However, HCPs should aim to minimise opioid use, which includes referring to specialist services, to reduce the likelihood of adverse events41In people with renal colic, fewer patients were in persistent pain after 60 minutes with diclofenac (24%) and paracetamol (30%) than morphine (38%)42.
The panel also discuss many of the nuances of using opioids, such as imputation as a source of bias, particularly in studies with a high rate of withdrawals because of adverse events, and pharmacogenetic determinants of unpredictable responses to codeine, which is metabolised by cytochrome 450 2D6 to morphine43,44.
The role of paracetamol
Does paracetamol have a role in managing severe pain?
This video discusses the risks and benefits of paracetamol (acetaminophen) in the management of severe, chronic pain.
A meta-analysis reported that paracetamol has no significant benefit on pain, quality of life or disability in low back pain. Paracetamol significantly reduced pain and disability in OA, but the size of the benefit was small and the clinical relevance of the improvement is unclear45. Moreover, paracetamol is associated with an increased risk of liver damage compared with NSAIDs38.
Top tips in pain management
This section includes helpful videos exploring the effect of NSAID formulation, a brief summary of the evidence, the interpretation of network meta-analyses, controversies in pain management and an Ask the Expert session.
Importance of NSAID formulation
Should diclofenac potassium be preferred over diclofenac sodium for acute pain relief?
Professors Moore and Göbel, and Dr Aldington discuss the effect that NSAID formulation can have on pain outcomes.
Professor Moore briefly summarises the state of the evidence for the management of acute post-operative pain, migraine and TTH, and acute musculoskeletal pain.
Role of network meta-analyses
How has the recent network meta-analyses data changed the perception of the risk-benefit profile of analgesics?
Professor Moore explores how network meta-analyses can compare analgesics including the relative efficacy, safety and tolerability of diclofenac, ibuprofen, naproxen, celecoxib, and etoricoxib for patients with pain arising from osteoarthritis or rheumatoid arthritis46.
Network meta-analyses compare multiple treatments in a single analysis by combining direct (e.g. randomised clinical trials) and indirect evidence using common comparators. For example, assume that one study compared analgesic A with analgesic B. Another study compared analgesics C and B. By using the common comparator (B), the network meta-analysis can estimate the relative effects of A versus C47.
Controversies in pain management
What are the current controversies in pain management?
Professors Moore and Göbel, and Dr Aldington discuss some controversies in pain management including combinations, the role of caffeine; cannabinoids, NSAIDs and renal function; whether NSAIDs are effective in fibromyalgia; and optimal care in patients with comorbidities.
Questions answered include:
- What are your thoughts on combination therapy with paracetamol and tramadol?
- Is diclofenac suitable for use in chronic fibromyalgia?
- Is paracetamol nephrotoxic?
- How do you treat a patient with RA who also has hepatitis?
- Is the combination of caffeine and ibuprofen related more to the management of postoperative pain or acute pain in general?
- Can you use NSAIDs instead of aspirin for cardio protection?
- Is there any duration of paracetamol use that is associated with nephrotoxicity?
- Can cannabinoids be valuable for treating pain?
- What is the best way to manage neurogenic/neuropathic pain?
Ask the expert: anything
In this interactive session, Professors Ebied, Özen and Pereira da Silva and Dr Singh respond to audience questions about non-pharmacological pain treatment, assessing NSAID adverse events, including renal function, and managing pain during pregnancy and in the post-operative setting.
- What about non-pharmacological options for pain management?
- What are the clinical and laboratory parameters used to study the side effects of NSAIDs in a patient with JIA?
- Do you routinely do renal function tests before starting diclofenac in every patient?
- What about Stevens-Johnson syndrome associated with NSAIDs? What is its prognosis?
- Can rheumatoid arthritis cause miscarriage?
- Do you stop methotrexate in the postoperative period?
- What would be your NSAID of choice in a patient with several comorbid conditions?
In the second question and answer session, Professors Moore and Dougados answer audience questions around the benefits and risks of various pain management treatments.
Questions were answered on the topics of:
- Use of paracetamol for severe chronic pain
- Safety of long term opioids in chronic pain
- Important comorbidities to consider when using NSAIDs
- Use of NSAIDs in aspirin-sensitive asthma
- Clinical factors to consider when prescribing NSAIDs
- Role of NSAIDs in chronic pain – combinations and antidepressants
- Effects of NSAIDs on fracture healing
- Duration of treatment with NSAIDs for chronic pain
- Gastrointestinal tolerability and combination with a proton pump inhibitor
- Factors to consider in managing pain in the elderly
- Cardiovascular risk with NSAIDs
Allegri M, Montella S, Salici F, Valente A, Marchesini M, Compagnone C et al. Mechanisms of low back pain: a guide for diagnosis and therapy. F1000Research. 2016;5:DOI: 10.12688/f1000research.8105.2
Anwar A, John Anwar I, and Delafontaine P. Elevation of cardiovascular risk by non-steroidal anti-inflammatory drugs. Trends in Cardiovascular Medicine. 2015;25:726-735
Ashburn MA and Fleisher LA. Perioperative opioid management — An opportunity to put the genie back into the bottle. JAMA Surgery. 2018;153:938
Bakland G, Gran JT, and Nossent JC. Increased mortality in ankylosing spondylitis is related to disease activity. Annals of the Rheumatic Diseases. 2011;70:1921-1925
Chappell AS, Desaiah D, Liu-Seifert H, Zhang S, Skljarevski V, Belenkov Y et al. A double-blind, randomized, placebo-controlled study of the efficacy and safety of duloxetine for the treatment of chronic pain due to osteoarthritis of the knee. Pain Practice. 2011;11:33-41
Collins SL, Moore RA, and McQuay HJ. The visual analogue pain intensity scale: What is moderate pain in millimetres? Pain. 1997;72:95-97
Coluzzi F, Valensise H, Sacco M, and Allegri M. Chronic pain management in pregnancy and lactation. Minerva Anestesiologica. 2014;80:211-224
Conaghan PG, Peloso PM, Everett SV, Rajagopalan S, Black CM, Mavros P et al. Inadequate pain relief and large functional loss among patients with knee osteoarthritis: evidence from a prospective multinational longitudinal study of osteoarthritis real-world therapies. Rheumatology. 2015;54:270-277
da Costa BR, Nüesch E, Kasteler R, Husni E, Welch V, Rutjes AWS et al. Oral or transdermal opioids for osteoarthritis of the knee or hip. The Cochrane Database of Systematic Reviews. 2014;CD003115-CD003115
de Tommaso M and Fernández-de-Las-Penas C. Tension type headache. Current Rheumatology Reviews. 2016;12:127-139
Elia N, Lysakowski C, and Tramèr MR. Does multimodal analgesia with acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone? Meta-analyses of randomized trials. Anesthesiology. 2005;103:1296-1304
Fayaz A, Croft P, Langford RM, Donaldson LJ, and Jones GT. Prevalence of chronic pain in the UK: A systematic review and meta-analysis of population studies. BMJ Open. 2016;6:DOI: 10.1136/bmjopen-2015-010364
Fillingim RB. Individual differences in pain: understanding the mosaic that makes pain personal. Pain. 2017;158 Suppl 1:S11–S18.
Fink R. Pain assessment: The cornerstone to optimal pain management. Proceedings (Baylor University. Medical Center). 2000;13:236-239
Giancane G, Alongi A, Rosina S, Calandra S, Consolaro A, and Ravelli A. Open issues in the assessment and management of pain in juvenile idiopathic arthritis. Clinical and Experimental Rheumatology. 2017;35 Suppl 107:123-126
Hanlon JT, Perera S, Newman AB, Thorpe JM, Donohue JM, Simonsick EM et al. Potential drug-drug and drug-disease interactions in well-functioning community-dwelling older adults. Journal of Clinical Pharmacy and Therapeutics. 2017;42:228-233
Hawker GA, Croxford R, Bierman AS, Harvey PJ, Ravi B, Stanaitis I et al. All-cause mortality and serious cardiovascular events in people with hip and knee osteoarthritis: A population based cohort study. PLOS One. 2014;9:e91286
Janke EA, Ramirez ML, Haltzman B, Fritz M, and Kozak AT. Patient’s experience with comorbidity management in primary care: A qualitative study of comorbid pain and obesity. Primary Health Care Research & Development. 2015;17:33-41
Jensen R and Stovner LJ. Epidemiology and comorbidity of headache. The Lancet Neurology. 2008;7:354-361
Krebs EE, Gravely A, Nugent S, Jensen AC, DeRonne B, Goldsmith ES et al. Effect of opioid vs nonopioid medications on pain-related function in patients with chronic back pain or hip or knee osteoarthritis pain: The SPACE randomized clinical trial. JAMA. 2018;319:872-882
Laitinen J, M.D. and Nuutinen L, M.D., Ph.D. Intravenous diclofenac coupled with PCA fentanyl for pain relief after total hip replacement. Anesthesiology. 1992;76:194-198
Lyngberg AC, Rasmussen BK, Jørgensen T, and Jensen R. Has the prevalence of migraine and tension-type headache changed over a 12-year period? A Danish population survey. European Journal of Epidemiology. 2005;20:243-249
Machado GC, Maher CG, Ferreira PH, Pinheiro MB, Lin C-WC, Day RO et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: Systematic review and meta-analysis of randomised placebo controlled trials. British Medical Journal. 2015;350:h1225
Marks JL, Colebatch AN, Buchbinder R, and Edwards CJ. Pain management for rheumatoid arthritis and cardiovascular or renal comorbidity. Cochrane Database of Systematic Reviews. 2011;DOI:10.1002/14651858.CD008952.pub2
Millea PJ and Brodie JJ. Tension-type headache. American Family Physician. 2002;66:797-804
Moore A, R., Derry S, Taylor RS, Straube S, and Phillips CJ. The costs and consequences of adequately managed chronic non-cancer pain and chronic neuropathic pain. Pain Practice. 2014;14:79-94
Moore RA, Cai N, Skljarevski V, and Tölle TR. Duloxetine use in chronic painful conditions – individual patient data responder analysis. European Journal of Pain. 2014;18:67-75
Moore RA, Derry S, Aldington D, and Wiffen PJ. Single dose oral analgesics for acute postoperative pain in adults - an overview of Cochrane reviews. The Cochrane Database of Systematic Reviews. 2015;2015:CD008659-CD008659
Moore RA, Derry S, Simon LS, and Emery P. Nonsteroidal anti-inflammatory drugs, gastroprotection, and benefit–risk. Pain Practice. 2014;14:378-395
Moore RA, Derry S, Wiffen PJ, Straube S, and Aldington DJ. Overview review: Comparative efficacy of oral ibuprofen and paracetamol (acetaminophen) across acute and chronic pain conditions. European Journal of Pain. 2015;19:1213-1223
Moore RA, Straube S, and Aldington D. Pain measures and cut-offs - 'no worse than mild pain' as a simple, universal outcome. Anaesthesia. 2013;68:400-412
Moore RA, Straube S, Eccleston C, Derry S, Aldington D, Wiffen P et al. Estimate at your peril: Imputation methods for patient withdrawal can bias efficacy outcomes in chronic pain trials using responder analyses. Pain. 2012;153:265-268
Mordecai L, Reynolds C, Donaldson LJ, and de C Williams AC. Patterns of regional variation of opioid prescribing in primary care in England: A retrospective observational study. British Journal of General Practice. 2018;68:e225-e233
National Institute for Health and Care Excellence. Identifying and Assessing Common Mental Health Disorders Last updated: 04 December 2018; Available at: pathways.nice.org.uk/pathways/common-mental-health-disorders-in-primary-care; Accessed: January 2020 2018;
Nissen SE, Yeomans ND, Solomon DH, Lüscher TF, Libby P, Husni ME et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. The New England Journal of Medicine. 2016;375:2519-2529
Nüesch E, Dieppe P, Reichenbach S, Williams S, Iff S, and Jüni P. All cause and disease specific mortality in patients with knee or hip osteoarthritis: Population based cohort study. British Medical Journal. 2011;342:d1165
Pariente G, Leibson T, Carls A, Adams-Webber T, Ito S, and Koren G. Pregnancy-associated changes in pharmacokinetics: A systematic review. PLoS Medicine. 2016;13:e1002160-e1002160
Pathan SA, Mitra B, Straney LD, Afzal MS, Anjum S, Shukla D et al. Delivering safe and effective analgesia for management of renal colic in the emergency department: A double-blind, multigroup, randomised controlled trial. Lancet. 2016;387:1999-2007
Rouse B, Chaimani A, and Li T. Network meta-analysis: An introduction for clinicians. Internal and Emergency Medicine. 2017;12:103-111
Schmidt M, Sørensen HT, and Pedersen L. Diclofenac use and cardiovascular risks: Series of nationwide cohort studies. BMJ. 2018;362:k3426
Smith HS. Opioid metabolism. Mayo Clinic Proceedings. 2009;84:613-624
Solomon DH, Rassen JA, Glynn RJ, Lee J, Levin R, and Schneeweiss S. The comparative safety of analgesics in older adults with arthritis. Archives of Internal Medicine. 2010;170:1968-1978
Straube S, Tramèr MR, Moore RA, Derry S, and McQuay HJ. Mortality with upper gastrointestinal bleeding and perforation: Effects of time and NSAID use. BMC Gastroenterology. 2009;9:41
Stubbs B, Aluko Y, Myint PK, and Smith TO. Prevalence of depressive symptoms and anxiety in osteoarthritis: A systematic review and meta-analysis. Age and Ageing. 2016;45:228-235
Studenic P, Radner H, Smolen JS, and Aletaha D. Discrepancies between patients and physicians in their perceptions of rheumatoid arthritis disease activity. Arthritis & Rheumatism. 2012;64:2814-2823
van Walsem A, Pandhi S, Nixon RM, Guyot P, Karabis A, and Moore RA. Relative benefit-risk comparing diclofenac to other traditional non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors in patients with osteoarthritis or rheumatoid arthritis: A network meta-analysis. Arthritis Research & Therapy. 2015;17:66
Vos T, Flaxman A, Naghavi M, Lozano R, Michaud C, Ezzati M et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2163-2196
Wadensten B, Fröjd C, Swenne CL, Gordh T, and Gunningberg L. Why is pain still not being assessed adequately? Results of a pain prevalence study in a university hospital in Sweden. Journal of Clinical Nursing. 2011;20:624-634