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Analgesics

Rheumatoid arthritis in adults: diagnosis and management

Evidence review G

NICE Guideline, No. 100

.

London: National Institute for Health and Care Excellence (NICE); .
ISBN-13: 978-1-4731-3003-6

1. Analgesics in Rheumatoid Arthritis

1.1. Review question: In adults with rheumatoid arthritis, what is the clinical and cost effectiveness of analgesics?

1.2. Introduction

Analgesics (including NSAIDs, paracetamol and opioids) are sometimes used on top of disease-modifying treatments for relief of pain and stiffness in people with rheumatoid arthritis (RA) whose symptom control is not adequate. The previous guideline recommended analgesics other than NSAIDs to reduce a person’s need for long term treatment with NSAIDs, and included cautionary recommendations about how and when NSAIDs should be used. However, the evidence on analgesia other than NSAIDs in the previous guideline was highly limited, meaning there is uncertainty about the effectiveness of different types of analgesia in rheumatoid arthritis. Given this uncertainty, the committee wished to update these recommendations to reflect the latest and most robust clinical evidence. The committee agreed to use the term NSAIDS to include both selective and non-selective COX II inhibitors.

1.3. PICO table

For full details, see the review protocol in appendix A.

Table 1. PICO characteristics of review question.

Table 1

PICO characteristics of review question.

1.4. Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual.21 Methods specific to this review question are described in the review protocol in appendix A.

Declarations of interest were recorded according to NICE’s 2014 conflicts of interest policy.

1.5. Clinical evidence

1.5.1. Included studies

A search was conducted for randomised controlled trials and systematic reviews of randomised controlled trials comparing analgesics with other analgesics (interclass) or placebo in adults with rheumatoid arthritis. Forty-eight studies were included in the review. However, only 41 of these studies reported results in a form that could be extracted and analysed in the review;7 ,11 ,20 ,23 ,30 ,33 ,35 ,40 ,50 ,56–58 ,69 ,72–75 ,80–82 ,85 ,93 ,98 ,106 ,108 ,111 ,113 ,114 ,116–118 ,128 ,131 ,168 ,169 ,180 ,185 ,190 ,191 ,193 ,194 these are summarised in Table 2 below. The studies reported a wide range of comparisons, as follows:

Interclass comparisons:

  • one study compared paracetamol with an NSAID
  • one study compared opioid plus paracetamol plus NSAID with an NSAID
  • one study compared an opioid plus an NSAID with an opioid plus paracetamol (no extractable data).

Placebo comparisons:

  • one study compared an opioid with placebo (no extractable data)
  • two studies compared opioid plus paracetamol with placebo
  • three studies compared tricyclic antidepressants with placebo (1 with extractable data)
  • thirty-nine studies compared an NSAID with placebo (36 with extractable data).

Evidence from these studies is summarised in the clinical evidence summary below (Table 3). See also the study selection flow chart in appendix B, forest plots in appendix D, study evidence tables in appendix E, GRADE tables in appendix G and excluded studies list in appendix H.

1.5.2. Excluded studies

See the excluded studies list in appendix I.

1.5.3. Summary of clinical studies included in the evidence review

Table 2. Summary of randomised controlled trials with extractable data included in the evidence review.

Table 2

Summary of randomised controlled trials with extractable data included in the evidence review.

See appendix D for full evidence tables.

1.5.4. Quality assessment of clinical studies included in the evidence review

Table 3. Clinical evidence summary: Paracetamol plus opioid plus NSAID versus NSAID.

Table 3

Clinical evidence summary: Paracetamol plus opioid plus NSAID versus NSAID.

Table 4. Clinical evidence summary: NSAID versus paracetamol.

Table 4

Clinical evidence summary: NSAID versus paracetamol.

Table 5. Clinical evidence summary: NSAIDs versus placebo.

Table 5

Clinical evidence summary: NSAIDs versus placebo.

Table 6. Clinical evidence summary: Tricyclic antidepressants versus placebo.

Table 6

Clinical evidence summary: Tricyclic antidepressants versus placebo.

Table 7. Clinical evidence summary: Paracetamol plus opioid versus placebo.

Table 7

Clinical evidence summary: Paracetamol plus opioid versus placebo.

See appendix F for full GRADE tables.

1.6. Economic evidence

1.6.1. Included studies

No relevant health economic studies were identified.

1.6.2. Excluded studies

No health economic studies that were relevant to this question were excluded due to assessment of limited applicability or methodological limitations.

See also the health economic study selection flow chart in appendix G.

1.6.3. Unit costs

Table 8. UK costs of analgesics.

Table 8

UK costs of analgesics.

1.7. Resource costs

The recommendations made in this review are not expected to have a substantial impact on resources.

1.8. Evidence statements

1.8.1. Clinical evidence statements

  • Paracetamol plus opioid plus NSAID versus NSAID

Evidence from 1 study showed that there was no clinically important difference between combined treatment with paracetamol, opioid and NSAID versus NSAID alone in terms of improving pain or discontinuation due to inefficacy; however, NSAID alone was associated with a clinically important benefit over the combination treatment in terms of discontinuation for adverse events (very low to moderate quality, n=60). No evidence was available for quality of life.

  • NSAID versus paracetamol

Evidence from 1 study showed a clinically important benefit of NSAIDs over paracetamol in terms of pain and discontinuation due to inefficacy; however, paracetamol was associated with a clinically important benefit over NSAIDs in terms of discontinuation for adverse events (low to very low quality, n=96). No evidence was available for quality of life.

  • NSAIDs versus placebo

NSAIDs were found to have a clinically important benefit in terms of discontinuations due to inefficacy. There was inconsistent evidence for the effect of NSAIDs versus placebo on pain, stiffness and function. Some measures of pain, stiffness and function showed a clinically important benefit of NSAIDs over placebo, but other measures of the same outcomes found no clinically important difference (reported in 11, 9 and 7 studies respectively; range of n=3,320-5,394; moderate to very low quality). NSAIDs were associated with a small but clinically important increased occurrence of 9 per thousand people in serious gastrointestinal events when compared to placebo (very low quality; 9 studies; n=5,072). No clinically important difference was seen for mortality, cardiac and vascular adverse events or discontinuation due to adverse events (reported in 5, 6 and 31 studies respectively; range of n= 2,895–10,288; very low quality). No evidence was available for quality of life.

  • Tricyclic antidepressants versus placebo

Evidence from 1 study comparing tricyclic antidepressants with placebo suggested that tricyclic antidepressants were associated with a clinically important benefit in terms of fewer discontinuations due to adverse events but a clinically important increase discontinuations due to inefficacy (very low quality; n=36). However, there was considerable uncertainty in the direction of the effects, limiting the ability to draw firm conclusions. No evidence was available for pain or quality of life.

  • Paracetamol plus opioid versus placebo

Evidence from 1 study suggested no clinically important difference between paracetamol plus opioid versus placebo in terms of pain but a clinically important benefit of paracetamol plus opioid in terms of function and discontinuation due to inefficacy (very low quality; n=277). Paracetamol plus opioid was associated with an increased occurrence of discontinuation due to adverse events (low quality; 2 studies; n=317). No evidence was available for quality of life.

1.8.2. Health economic evidence statements

No relevant economic evaluations were identified.

1.9. The committee’s discussion of the evidence

1.9.1. Interpreting the evidence

1.9.1.1. The outcomes that matter most

The committee agreed that the critical outcomes for decision-making were quality of life and pain. Stiffness and function were included as important outcomes. In addition, medication continuation and adverse events (mortality, serious gastrointestinal events, serious cardiac and vascular events, and impaired renal function) were considered important outcomes.

The committee agreed that pain, quality of life, stiffness and function should be reported at 3 different time points to enable judgement of efficacy across short or longer treatment periods. Therefore, the results were separated into 3 time periods: less than or equal to 2 weeks, greater than 2 weeks and up to and including 6 weeks, and more than 6 weeks.

No evidence was found for quality of life for any of the analgesic drugs considered.

1.9.1.2. The quality of the evidence

The majority of the evidence received a GRADE quality rating of low or very low. None of the evidence was considered high quality. Risk of bias was high or very high for all outcomes for reasons including selection bias due to no details of how randomisation was conducted or whether there was allocation concealment, lack of details about how blinding was carried out for subjective outcomes, and missing data due to treatment discontinuation. There were a small number of outcomes which contained inconsistent results that could not be explained by subgroup analysis.

Four studies in the NSAID versus placebo comparison were considered to have indirect populations due to participants being required to have a history of positive response to previous treatment with NSAIDs. Also, the lack of protein pump inhibitor (PPI) treatment in all of the non-selective COX II inhibitor NSAID studies led to gastrointestinal adverse event outcomes being considered indirect evidence. The BNF states that people at risk of gastro-intestinal ulceration (including the elderly), who use NSAID treatment, should receive gastroprotective treatment.

1.9.1.3. Benefits and harms
NSAIDs

The committee acknowledged that the evidence for NSAIDs compared to placebo was inconsistent in terms of pain relief, with the magnitude of the effect varying depending on the scoring system used. In general, NSAID treatment seemed to provide some reduction in pain but the results were often not sufficiently large to be considered clinically important. There was also some evidence of benefit of NSAIDs on stiffness and function (though this was somewhat inconsistent), and a clinically important reduction in people discontinuing due to inefficacy when taking NSAIDs compared to placebo. Overall, the committee’s view was that NSAIDs may offer a small benefit in relieving symptoms for adults with RA. The 3 timepoints which data was separated into did not give an explanation of when NSAIDs were effective analgesics.

The committee discussed the evidence on adverse events of NSAIDs. There was no clinically important difference between NSAIDs and placebo for most adverse events (mortality, cardiac and vascular events, impaired renal function and discontinuation due to adverse events). However, NSAIDs were associated with an increased risk of serious gastrointestinal events. The committee noted that the absolute risk was small and on balance, the committee agreed that the benefit of NSAIDs for people whose symptom control is not adequate was likely to outweigh the risk of harm. The committee also noted that the risk of GI events may have been overestimated in the evidence as PPIs were not co-prescribed with non-selective NSAIDs in the included studies. Overall, the committee recommended that oral NSAIDs be considered in people with rheumatoid arthritis whose symptom control is not adequate.

The committee discussed whether the recommendation for NSAIDs should include the stipulation that PPIs be co-prescribed, as was recommended in the 2009 guideline and agreed this should remain.

To minimise the risk of adverse events, the committee agreed that NSAIDs should be used at the lowest doses and for the shortest possible time, and that risk factors for adverse events should be reviewed regularly, these include previous peptic ulcer, age over 60 years, use of oral steroids, anticoagulants and/or anti-platelet (aspirin or clopidogrel).

Other analgesics

The committee discussed the evidence for other analgesic treatments and noted that it was highly limited.

Paracetamol plus opioid treatment was compared with placebo in 2 studies. The combined treatment showed a clinical benefit over placebo for function and was associated with a clinically significant reduction in discontinuations due to inefficacy. However, it failed to show a benefit over placebo for the critical outcome of pain. It also showed a benefit over placebo in terms of fewer discontinuations due to adverse events, the GC considered this an unlikely finding which only served to highlight the weaknesses of the evidence.

Single small studies provided limited evidence for each of the following comparisons: tricyclic antidepressants versus placebo, NSAID versus paracetamol, and NSAID versus paracetamol plus opioid plus NSAID. The committee placed little weight on the highly limited, poor quality and inconsistent evidence for these comparisons. No evidence was found for nefopam, gabapentinoids or SSRI and SSNRI antidepressants.

The committee noted the 2009 recommendations to use analgesics other than NSAIDs (such as paracetamol, codeine or compound analgesics) which, at the time, was acknowledged to be based on “sparse” evidence. The committee discussed the evidence on the other analgesic treatments and decided that it was too weak to support recommendations for or against their usage. Therefore the 2009 recommendation was not sustained though a research recommendation investigating non-NSAID analgesic drugs was submitted.

General

The committee agreed that choice of analgesic tends to be based on individual effectiveness as well as the person’s risk profile, tolerance, and side effects. In particular, there are some groups of people for whom NSAIDs are unsuitable because of contraindications, comorbidities or tolerability, and other people who are currently benefiting from analgesic drugs other than NSAIDs. The committee agreed that these recommendations should not change the current individualised approach to analgesic drug choice. The committee agreed, based on their experience, that compound analgesics in particular were a potentially useful analgesic option in rheumatoid arthritis, notwithstanding the evidence being insufficient to support a recommendation.

The committee noted that there was a body of evidence on the usage of NSAIDs for short term symptom control but other analgesic drugs, such as paracetamol plus opioid, have not been adequately studied in rheumatoid arthritis. The committee agreed that the effectiveness of non NSAID analgesic drugs in controlling rheumatoid arthritis symptoms was a high priority for further research. Few studies were found for treatment strategies not utilising NSAIDs and the committee decided to make a research recommendation in this area to inform future guidance on analgesia in rheumatoid arthritis.

1.9.2. Cost effectiveness and resource use

No relevant published economic evidence was identified.

The committee noted that NSAIDs are currently used by people with rheumatoid arthritis and are available either under prescription or over the counter. The committee highlighted that, although their unit cost is relatively low, follow-up costs due to adverse events may increase the NHS resource use in a small group of patients. The committee believed though that, if NSAIDs are offered at their lowest effective dose and for the shortest period possible, the benefits from using them to alleviate disease symptoms outweigh their overall costs.

The committee highlighted that the current approach is likely to continue but there may be an increase in prescribing of NSAIDs instead of other analgesic drugs for people with newly diagnosed RA. Overall however, the recommendation is not expected to have a significant resource impact to the NHS.

1.9.3. Other factors the committee took into account

The management of rheumatoid arthritis in pregnancy was identified as an equalities issue in the equalities impact assessment. No evidence was found for this population strata. The committee agreed that it should be an individualised and consultant-led service, with involvement of obstetric services and broader rheumatology MDT as indicated. Patients and their rheumatology team need to consider many aspects of each individual person’s care. These include pre-conception advice and management of pharmacological therapies, assessment of potential impact of disease on the pregnancy, advice on disease course during pregnancy, and discussions regarding the disease and its treatment in the post-partum period. Particular attention should be paid to therapeutic management of rheumatoid arthritis to ensure potentially teratogenic therapies are not continued in the pre-conception stage or into early pregnancy. Alternative management strategies should be considered, depending on each patient’s level of disease control and symptoms, for the duration of the pregnancy.

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Appendices

Appendix A. Review protocols

Table 9. Review protocol: Analgesics (PDF, 191K)

Table 10. Health economic review protocol (PDF, 152K)

Appendix B. Literature search strategies

The literature searches for this review are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual 2014, updated 2017

(https://www.nice.org.uk/guidance/pmg20/resources/developing-nice-guidelines-the-manual-pdf-72286708700869).

For more detailed information, please see the Methodology Review.

B.1. Clinical search literature search strategy

Searches were constructed using a PICO framework where population (P) terms were combined with Intervention (I) and in some cases Comparison (C) terms. Outcomes (O) are rarely used in search strategies for interventions as these concepts may not be well described in title, abstract or indexes and therefore difficult to retrieve. Search filters were applied to the search where appropriate.

Table 11. Database date parameters and filters used

Medline (Ovid) search terms

Embase (Ovid) search terms

Cochrane Library (Wiley) search terms

B.2. Health Economics literature search strategy

Health economic evidence was identified by conducting a broad search relating to rheumatoid arthritis population in NHS Economic Evaluation Database (NHS EED – this ceased to be updated after March 2015) and the Health Technology Assessment database (HTA) with no date restrictions. NHS EED and HTA databases are hosted by the Centre for Research and Dissemination (CRD). Additional searches were run on Medline and Embase for health economics studies.

Table 12. Database date parameters and filters used

Medline (Ovid) search terms

Embase (Ovid) search terms

NHS EED and HTA (CRD) search terms

Appendix D. Clinical evidence tables

Download PDF (932K)

Appendix E. Forest plots

Appendix G. Health economic evidence selection

Figure 29. Flow chart of economic study selection for the guideline

Appendix H. Health economic evidence tables

None.

Appendix I. Excluded studies

I.2. Excluded health economic studies

None.

Appendix J. Research recommendations

J.1. Analgesic drugs

Research question: What is the clinical and cost effectiveness of analgesic drugs other than non-steroidal anti-inflammatory drugs (NSAIDs) in adults with rheumatoid arthritis (RA) whose pain or stiffness control is not adequate?

Why this is important

Analgesics (including NSAIDs, paracetamol, opioids and compound analgesics) are sometimes used in addition to disease-modifying treatments for relief of pain and stiffness in people with rheumatoid arthritis whose symptom control is not adequate. Current practice regarding the choice of analgesic in RA is variable. The evidence base for many of the analgesic drugs in RA (other than NSAIDs) is limited, and thus their relative effectiveness is unknown. Further research in this area may enable the guideline to make recommendations about the use of analgesic drugs other than NSAIDs.

Criteria for selecting high-priority research recommendations
PICO question

Population: Adults with rheumatoid arthritis whose symptom control is inadequate

Intervention(s): Analgesic drugs, for example paracetamol and codeine (excluding NSAIDs)

Comparison: NSAIDs / COX II selective inhibitors

Outcome(s): Pain, function, stiffness and quality of life

Importance to patients or the populationIf unresolved pain can be improved with an acceptable level of side effects, a significant improvement in patient-related outcomes such as function and quality of life would be expected. In addition, many people with RA are currently taking analgesics that are not specifically recommended in the guideline due to a lack of evidence, such as compound analgesics like paracetamol and codeine. Better knowledge of the effectiveness of these drugs would be of benefit to people with RA as it will improve shared decision making on their best treatment options.
Relevance to NICE guidanceCurrent guidance is to consider NSAIDs for people with RA whose symptom control is inadequate. No recommendations were made on the use of other analgesic drugs, including paracetamol and codeine, due to the paucity of evidence. Further research on these other analgesic drugs may enable recommendations on their use to be included in future updates of the guideline.
Relevance to the NHSBetter management of symptoms in people with RA would likely improve people’s quality of life and reduce length of routine appointments. The use of these medications, should they be found to be beneficial, would not have a significant financial impact on the NHS.
National prioritiesN/A
Current evidence baseHigh quality evidence for analgesic medication other than NSAIDs in RA is lacking.
EqualityNone
Study designRandomised controlled trial (double dummy non-inferiority trial) comparing analgesic drugs with NSAIDs in addition to conventional management (e.g. DMARDs). Participants in each arm should have stable RA, in remission (on a stable DMARD regime), with equal concomitant treatment options available to each group.
FeasibilityThis has been designed as a head to head trial to improve feasibility as a placebo controlled trial is likely to be difficult to recruit sufficient numbers. Pharmacological funding for a trial such as this is unlikely due to the drugs being generic and widely available, therefore funding could provide a challenge if not available through non-commercial funders.
Other commentsUnresolved pain is an increasingly recognised problem in adults with rheumatoid arthritis. The importance of this issue means it should be on research agendas of multiple funding agencies.
ImportanceModerate: the research is of interest and will fill existing evidence gaps.

Final

Evidence review

Developed by the National Guideline Centre, hosted by the Royal College of Physicians

The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and, where appropriate, their carer or guardian.

Local commissioners and providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Copyright © NICE 2018.
Bookshelf ID: NBK577153PMID: 35129928

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