Although pre-operative risk factors for chronic pain after total knee replacement have been explored extensively, post-operative risk factors have not.
Treatments in the pathway through total knee replacement may potentially modify risk factors for poor patient outcomes and adverse events. These have been reviewed previously, but not with an emphasis on chronic pain.
Little research has focused on the treatment of chronic pain after knee replacement.48 Interventions for the management of chronic pain after other surgeries may have value in the context of total knee replacement.
Risk factors for chronic pain after total knee replacement: systematic review
This section has been published as Wylde et al.88
Aims
This systematic review aimed to identify early post-operative patient-related risk factors for chronic pain after total knee replacement.
Methods
A prospectively registered systematic review (PROSPERO CRD42016041374),89 was conducted and reported as recommended by PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.90 We searched MEDLINE, EMBASE and PsycINFO from inception to October 2016 with no language restrictions (see Appendix 2, Systematic review search strategy as applied in MEDLINE on Ovid).
Eligible studies were longitudinal in design and met the following inclusion criteria:
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patients observed within 3 months of knee replacement
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intervention group – people with a risk factor
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control group – non-exposed people
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outcome – chronic pain at ≥ 6 months after knee replacement
Risk of bias was assessed with a non-summative checklist (Box 2),87 based on components of the methodological index for non-randomized studies (MINORS)91 and Newcastle-Ottawa Quality Assessment Scale.92 Results were reported as a descriptive narrative analysis.
Four-point system for assessing risk of bias in cohort studies
Results
Searches identified 14 cohort studies (1168 patients) evaluating the association between patient-related factors in the first 3 months post operation and pain at ≥ 6 months after primary total knee replacement (see Appendix 2, ).
Risk factors for chronic pain after total knee replacement: systematic review flow diagram. TKR, total knee replacement.
Post-operative patient-related factors evaluated included acute pain (eight studies), function (five studies) and psychosocial factors (four studies). In studies with no risk of bias other than patient selection, there was a suggestion that acute post-operative pain during the hospital stay was associated with chronic pain.52,93 However, in one of these studies, the association was largely explained by pre-operative pain.52 For all other post-operative patient factors, there was insufficient evidence to draw firm conclusions about an association with chronic pain after total knee replacement.
Risk factors for chronic pain after total knee replacement: database analyses
The NJR/HES analyses are published as Khalid et al.94 and the HES/CPRD/PROMs analyses are published as Mohammad et al.95
Aims
These analyses of national databases aimed to identify early risk factors for chronic pain after total knee replacement.
Methods: analysis 1
Primary knee replacements recorded in the NJR were linked with the HES and PROMs databases. We identified primary elective knee replacements performed between April 2008 and December 2016. Predictor variables within 3 months post surgery were surgical complications (i.e. fracture, patella tendon avulsion or ligament injury), medical complications (i.e. myocardial infarction, stroke, acute renal failure, deep-vein thrombosis or pulmonary embolism, surgical site infection, respiratory infection, urinary tract infection, wound disruption, mechanical complication of prosthesis, fracture, neurovascular injury, or blood transfusion), length of stay, readmission, reoperation or revision. The outcome was chronic pain measured using the OKS at 6 months after surgery. The associations of the predictors with the chronic pain outcome were explored using logistic regression modelling.
Methods: analysis 2
We conducted a retrospective observational study using anonymised data from the CPRD GOLD database linked to the HES and PROMs databases. Patients were identified using the CPRD GOLD database of individual patient data from electronic primary health-care records from practices across the UK.96 The CPRD provides a detailed record of both primary and secondary care.97 Primary care records from the CPRD were linked to secondary care admission records from HES Admitted Patient Care data and the Office for National Statistics mortality data. HES also provides PROMs data before and 6 months after knee replacements.
We included all patients receiving a primary knee replacement between 2009 and 2016. Inclusion in the analysis was limited to patients with HES-linked data (i.e. those in England only) who completed both the pre- and 6-month-post-operative OKS pain subscale (OKS-PS).80
The treatment effect [(pre-treatment OKS-PS score – post treatment OKS-PS score)/pre-treatment OKS-PS score]98,99 was calculated for each patient. A treatment effect of ≤ 0.2 was used to classify patients as non-responders to surgery regarding their knee pain. Relative risk ratios were generated by fitting a generalised linear model with a binomial error structure and a log link function (log-logistic model) and adjusted risk differences (ARDs) estimated from marginal effects from the regression model.
Results: analysis 1
Pre- and 6-month-post-operative OKSs were available for 258,386 patients and 43,702 (16.9%) of these were identified as having chronic pain at 6 months post surgery. Within 3 months of surgery, complications were uncommon: there were surgical complications in 1224 (0.5%) patients, one or more medical complications in 6073 (2.4%) patients, readmissions to hospital in 32,930 (12.7%) patients, knee-related reoperation in 848 (1.5%) patients and revision knee replacement operation in 835 (0.3%) patients. Post-operative predictors of chronic pain were mechanical complication of prosthesis [odds ratio (OR) 1.56, 95% confidence interval (CI) 1.35 to 1.80], surgical site infection (OR 1.13, 95% CI 0.99 to 1.29), readmission (OR 1.47, 95% CI 1.42 to 1.52), reoperation (OR 1.39, 95% CI 1.27 to 1.51), revision (OR 1.9, 95% CI 1.64 to 2.25) and length of hospital stay ≥ 6 days (OR 1.48, 95% CI 1.35 to 1.63). Predictive ability of the model was fair, with an area under the receiver operating characteristic (ROC) curve of 0.71, indicating that in respect of discriminatory ability, post-surgical predictors explain a limited amount of variability in chronic pain outcome.
Results: analysis 2
Information was available for 4750 patients between 2009 and 2016. Patients had a mean age of 69 years (standard deviation 9 years) and 56.1% were female. At 6 months after surgery, 10.4% of patients were classified as non-responders. The strongest associations with a non-response to surgery were seen for pre-operative risk factors; these were having only mild knee pain symptoms at the time of surgery (ARD 18.2%, 95% CI 13.6% to 22.8%), smoking (ARD 12.0%, 95% CI 7.3% to 16.6%), living in the most deprived areas (ARD 5.6%, 95% CI 2.3% to 9.0%) and obesity class II (i.e. body mass index between 35 and 40 kg/m2; ARD 6.3%, 95% CI 3.0% to 9.7%). We also identified a range of other risk factors with more moderate effects, including a history of knee arthroscopy surgery (ARD 4.6%, 95% CI 2.5% to 6.6%) and the use of opioids within 3 months after surgery (ARD 3.4%, 95% CI 1.4% to 5.3%).
Effectiveness of interventions to prevent chronic pain after total knee replacement: systematic reviews
These reviews have been published as Wylde et al.,100 Beswick et al.,101 and Dennis et al.102 A comprehensive overview has been published as Wylde et al.103
Aim
These systematic reviews aimed to assess the effectiveness of pre-, peri- and post-operative interventions in preventing chronic pain in patients receiving total knee replacement.
Workshop
In March 2016, 57 invited experts and colleagues met with the STAR team at a workshop to discuss interventions for the prevention of chronic pain after knee replacement. Those attending included surgeons, anaesthetists, physiotherapists, nurses and former patients, as well as researchers with interests in randomised trials, health economics, qualitative studies, PPI, systematic reviews and cohort studies.
The systematic review work package lead explained that the aim of the systematic reviews was to identify interventions that may improve long-term pain outcomes after knee replacement. The following definition of an intervention was presented:
Any clinical treatment or public health measure designed to reduce the incidence or modify the effects of particular diseases.
Yarnell and O’Reilly
104
Workshop participants considered that aspects of pre-operative care were potential targets for an intervention to prevent long-term pain. Many patients receive pre-operative education at a single class and from information booklets. Changes to content and interventions to improve uptake of classes were seen as potentially valuable. Pre-operative interventions might include cognitive behavioural therapy, self-management and peer support, weight management, exercise, treatment of comorbidities, nutritional guidance, and intra-articular injections. A multimodal approach might include education, psychological support, management of comorbidities and other components.
In the peri-operative period, workshop participants considered effective pain management important, possibly using gabapentin, nerve blocks and multimodal approaches. Certain anticoagulants are associated with micro-bleeds, which may lead to long-term pain. The use of tourniquets may also be associated with long-term pain.
An enhanced recovery protocol was considered a possible intervention to limit long-term pain. After hospital discharge, workshop participants noted the potential value of mid-term rehabilitation, peer support groups, provision of contact points, an introduction to community services and online resources, and psychological support including cognitive behavioural and mindfulness therapies. Provision of physiotherapy in different formats was also recognised as worth evaluating. Other interventions suggested were intra-articular injections, weight management, podiatry and realignment.
Methods
The systematic reviews were registered prospectively as PROSPERO CRD42017041382.105 We established a database of all randomised controlled trials and systematic reviews in total knee replacement. These were identified through searches of The Cochrane Library, MEDLINE, Embase, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and PsycINFO® (American Psychological Association, Washington, DC, USA) in November 2016 (updated February 2018 for peri-operative interventions and December 2018 for pre-operative interventions) (see Appendix 3, Systematic review search strategy as applied in MEDLINE on Ovid).
Eligible studies were randomised controlled trials that met the following inclusion criteria:
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patients with osteoarthritis awaiting or who have received total knee replacement
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intervention – treatment in the pre-, peri- or post-operative setting
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control – usual care or alternative treatment
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outcomes – chronic pain at ≥ 6 months after knee replacement (≥ 12 months for post-operative interventions), adverse events.
The database was screened, and interventions divided into pre-, peri- and post-operative contexts, and into intervention groups. Risk of bias was assessed using the Cochrane tool.106
Results: pre-operative interventions
Eight randomised controlled trials with nine comparisons (960 patients) were eligible (see Appendix 3, ). There was moderate-quality evidence of no effect of exercise programmes on chronic pain after total knee replacement, based on a meta-analysis of six interventions with 229 participants (standardised mean difference 0.20, 95% CI –0.06 to 0.47; I2 = 0%). A sensitivity analysis restricted to studies at low risk of bias confirmed these findings. Studies evaluating a combined exercise and education intervention (one study) and education alone (one study) suggested similar findings.
Effectiveness of pre-operative interventions: systematic review flow diagram. RCT, randomised controlled trial.
Results: peri-operative interventions
Forty-four randomised controlled trials at low risk of bias evaluated interventions in the peri-operative setting with a pain outcome or score with a pain component at ≥ 6 months’ follow-up (see Appendix 3, ). Intervention heterogeneity precluded meta-analysis. There was weak evidence for small reductions in chronic pain after total knee replacement in people who received peri-operative local infiltration analgesia (three studies), ketamine infusion (one study) or pregabalin (one study). Supported early discharge (one study) showed weak evidence of a small reduction in chronic pain. More clinically important benefits were seen for electric muscle stimulation (two studies), gait training (one study) and a course of anabolic steroids (one small pilot study).
Effectiveness of peri-operative interventions: systematic review flow diagram.
For a range of peri-operative treatments there was no evidence linking them with unfavourable pain outcomes. For example, blood conservation with tranexamic acid during knee replacement was not associated with chronic pain. However, otherwise extensively researched interventions including venous thromboembolism prevention and tourniquet use have not been evaluated in relation to chronic pain.
Results: post-operative interventions
Randomised controlled trials of post-discharge interventions commencing in the first 3 months after total knee replacement were included (see Appendix 3, ). Seventeen trials with 2485 participants were included. All studies were at risk of bias because participants were not blinded to arm allocation, and five because of incomplete outcome data. Twelve trials evaluated physiotherapy interventions. Other interventions were nurse-led telephone follow-up, neuromuscular electrical stimulation and a multidisciplinary intervention. One study showed benefit for home-based exercises aimed at managing kinesophobia in reducing pain severity compared with no intervention. Otherwise, narrative synthesis found no evidence that one type of physiotherapy intervention is more effective than another. A 10-day multidisciplinary outpatient rehabilitation programme provided between 2 and 4 months after surgery showed no long-term benefit for pain or function.107 For other interventions, there was insufficient evidence to draw conclusions about effectiveness.
Effectiveness of post-operative interventions: systematic review flow diagram. RCT, randomised controlled trial; TKR, total knee replacement.
Effectiveness of interventions to manage chronic pain after surgery: systematic review
This review has been published as Wylde et al. 2017.108
Aims
This systematic review aimed to assess the efficacy of interventions to treat chronic pain after non-cancer surgeries.
Methods
The systematic review was registered prospectively as PROSPERO CRD42015015957.109 We searched MEDLINE, Embase, PsycINFO, CINAHL and The Cochrane Library from inception to March 2016 (see Appendix 4, Systematic review search strategy as applied in MEDLINE on Ovid). An update in October 2020 was timed to contextualise the STAR intervention.
Eligible studies were randomised controlled trials that met the following inclusion criteria:
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patients with chronic pain after non-cancer surgery
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an intervention for pain received by patients at a minimum of 3 months after surgery
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a comparator of no treatment, placebo, usual care or alternative treatment
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an outcome relating to pain.
Risk of bias was assessed using the Cochrane tool.106
Results
As shown in Appendix 4, , 66 trials with data from 3149 participants were included. Most trials included patients with chronic pain after spinal surgery (n = 25) or amputation (n = 21). Interventions were antiepileptics, capsaicin, epidural steroid injections, local anaesthetic, neurotoxins, opioids, acupuncture, exercise, spinal cord stimulation, further surgery, laser therapy, magnetic stimulation, mindfulness-based stress reduction, mirror therapy and sensory discrimination training. Opportunities for meta-analysis were limited by heterogeneity. For all interventions, there was insufficient evidence to draw conclusions on effectiveness but the review provided clear suggestions for future research.
Effectiveness of interventions to manage chronic pain after surgery: systematic review flow diagram. RCT, randomised controlled trial.
Review update
To examine the STAR trial in a contemporary context, we updated searches with terms relating to arthroplasty of the large joints, post-surgical pain, and randomised controlled trials (see Appendix 5, Systematic review search strategy as applied in MEDLINE on Ovid). Systematic reviews and trial registries were checked for studies.
Eligible studies were randomised controlled trials that met the following inclusion criteria:
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patients with chronic pain after arthroplasty of the large joints
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intervention – treatment for chronic pain
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control – no treatment, usual care or alternative treatment
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outcome – pain.
Of 3901 articles identified and screened by one reviewer, 69 were potentially relevant (see Appendix 5, ). After detailed evaluation by two reviewers, four published randomised evaluations of treatments for chronic pain after knee replacement were identified in the original review and update (see Appendix 5, ). No study was judged to be at high risk of bias. For people with general chronic pain, there were encouraging findings warranting further research into intra-articular botulinum toxin110 and denervation therapy.111 Radiofrequency genicular nerve treatment showed similar outcomes to treatment with anaesthetic and corticosteroid.112 No studies were found that evaluated a multifaceted intervention, but one study focusing specifically on treatment of neuropathic pain with topical lidocaine suggested that further research is merited for this personalised treatment.113
Interventions to manage chronic post-surgical pain update: systematic review flow diagram. RCT, randomised controlled trial.
Details of included studies
In addition to the STAR trial, six studies were ongoing or not published (see Appendix 5, ). These focus on exercise and education,114 cannabinoids,115 phenol neurolysis of genicular nerves,116 genicular nerve blocks117,118 and pulsed electromagnetic field therapy,119 all in people with general chronic pain after knee replacement.
Strengths and limitations
Our systematic reviews benefited from comprehensive literature searches and broad inclusion criteria to allow for evaluation of diverse interventions. Reviews were conducted according to appropriate guidelines and issues that may have introduced bias were considered. Meta-analysis was conducted, but only when appropriate. A narrative descriptive approach was used in circumstances of high heterogeneity of risk factors, interventions, outcomes and follow-up. Authors were contacted for clarification and missing information at all stages of the reviews. In the review of post-operative risk factors, a limited range of risk factors had been studied. In intervention reviews, our focus was on chronic pain as an outcome, which, although important, may not have been the specific outcome targeted by an intervention.
A strength of our database analyses was the large numbers of patients with linked data. Analyses included multiple centres and results should be generalisable throughout the NHS. Our analyses were limited by the content of data sets. Factors not recorded included implant positioning and surgical technique, pain management and medication use, and psychological, genetic, and environmental factors. Analyses were also limited by the single post-operative knee pain measure, which may not reflect established chronic pain.
Conclusions and inter-relationship with other parts of the programme
Before our comprehensive database analyses, knowledge of post-operative risk factors was limited to the observation that people with acute pain after knee replacement were more likely to report chronic pain. Risk factors identified in database analyses that may have potential for modification or use in the targeting of care included some patient and surgical factors, previous knee arthroscopy, use of opioids and surgical complications.
Randomised trials to assess long-term outcomes after pre-, peri- and post-operative interventions are feasible and necessary to ensure that patients receive care with reduced or no risk of chronic pain. Unifactorial interventions identified in systematic reviews and suggested by stakeholders merit further study.
Although some management strategies for chronic pain after diverse surgeries identified in our systematic review may have limited applicability outside the specific condition for which they were intended, others may be transferable regardless of the surgical procedure. Their value in the personalised prevention of chronic pain requires further research on their individual effectiveness and ultimately their potential as a component in a multifactorial care pathway.
