Diagnosis and management of neuropathic pain post-total knee replacement: A systematic review

Abstract

BACKGROUND

Neuropathic pain is common after total knee replacement (TKR), with incidence between 5% and 50%, but its identification, grading and treatment effectiveness remain unclear. The burden is high as the prevalence of TKR is 137 TKR/100000 across 33 countries (2019, Organisation for Economic Co-operation and Development).

AIM

To identify effective diagnosis and management of neuropathic pain after TKR the literature was systematically reviewed.

METHODS

We followed Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and registered in International Prospective Register of Systematic Reviews (No. CRD42021273288). Seven databases (MEDLINE, Cochrane Central, EMBASE, CINAHL, Emcare, Clinicaltrials.gov and World Health Organization International Clinical Trials Registry) were searched on Augst 19, 2021 (updated December 9, 2024) for studies reporting outcomes of treatment of neuropathic pain after TKR. The primary outcome was pain severity at 6-12 months. Papers were independently screened by three reviewers and risk of bias assessed. Data on population, interventions, duration of follow up, attrition and outcomes were extracted.

RESULTS

Of 7025 publications, 38 met the inclusion criteria. Seven studies were identified reporting different treatments and two randomized controlled studies were of good quality and low bias. Only two report a Visual Analogue Scale standardized mean difference of > 2 points at 6-12 months. The data on proportions with neuropathic pain could not be extracted in 5 of 7 papers. Data did not permit meta-analysis so synthesis without meta-analysis recommendations in reporting outcomes were followed. Three papers addressed interventions on the peripheral sensory nerve reporting improvement (hydro-dissection, resection or resisting of peripheral nerve, nerve block and neurectomy). Two studies investigated modifying the dorsal root ganglia with either radiofrequency ablation or transcutaneous electrical nerve stimulation. Two studies addressed modifying central sensitization; one reporting benefit.

CONCLUSION

This review identifies a considerable evidence gap for treatment effectiveness of post-TKR neuropathic pain. Studies are heterogenous in case definition, severity assessment and outcomes reported, which precludes treatment recommendations. A possible management pathway is outlined but requires validation. Future studies should report proportions with neuropathic pain and pain severity to 1-2 years post-treatment.

Key Words: Total knee replacement; Neuropathic pain; Arthroplasty; Systematic review; Diagnosis and management

Core Tip: Total knee replacements (TKRs) are a common procedure and the incidence of neuropathic pain post-TKR has been reported as up to 50%. The literature on diagnosis and management of neuropathic pain post-TKR was systematically reviewed. Seven eligible studies had different case definitions, severity assessment and outcomes reported. Current evidence does not support clear treatment recommendations for these patients. A possible logical pathway based on the current literature is outlined, but needs evidence of effectiveness for each step.

INTRODUCTION

Neuropathic pain, defined as pain ‘arising as a direct consequence of a lesion or disease affecting the somatosensory system’, can present with burning and shooting pain, allodynia and/or hyperalgesia[1]. Patients with neuropathic pain have poorer quality of life than those with non-neuropathic pain. Neuropathic pain is diagnosed using questionnaires - the Douleur-Neuropathique-4 (DN4)[2], Self-reported Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS)[3] and Identification Pain questionnaire[4] questionnaires are three screening tools and the PainDETECT[5] screens and assesses severity.

Neuropathic pain is not effectively treated with standard analgesia and specific management uses medications (pregabalin and gabapentin), topical agents (capsaicin creams, lidocaine plasters), and surgery. Also, the cause must be identified and managed if possible. Total knee replacement (TKR) is common [incidence of (52-240)/100000/year][6]. Between 2021 and 2023, 255743 TKRs were done in the United Kingdom[7]. Chronic pain lasting over three months after TKR occurs in 8% to 34%. There are many possible causes of chronic pain. Most represent nociceptive pain (e.g. patellofemoral joint pain, non-specific aching, referred pain from the hip or spine) in addition to neuropathic pain[8]. Patients may have more than one cause contributing to chronic pain after TKR.

One study reported neuropathic pain after TKR in 5% after six months, and another in up to 50%[9]. Phillip et al[10] reported the incidence of neuropathic pain after TKR at 6 weeks as 35%(30/85) using PainDETECT. At 46 months, this had decreased to 14%. Relative pain reduction of around 30% of baseline is meaningful improvement[1]. The prevalence of patients experiencing neuropathic pain is high but the identification and effectiveness of management pathways are uncertain as clinicians focus on implant failure.

After TKR neuropathic pain detection, severity assessment, natural history, expected benefits and harms of interventions remain unclear. The literature on neuropathic pain after TKR was systematically reviewed to establish diagnosis criteria, severity assessment and effectiveness of interventions.

MATERIALS AND METHODS

Study design

The study protocol was developed and submitted to Prospero Prospective Register of Systematic Reviews (No. CRD42021273288) before the review. Databases searched included MEDLINE, Cochrane Central, EMBASE, CINAHL, Emcare, Clinicaltrials.gov and World Health Organization International Clinical Trials Registry (Augst 19, 2021 and updated on December 9, 2024) for publications on neuropathic pain after TKR. The references of eligible studies were reviewed to identify further studies. The search strategy and checklists are presented in the Supplementary material.

The inclusion criteria were that studies reported the management of neuropathic pain post-TKR in adult patients (> 18 years); language was not restricted, and English translation were obtained for foreign language papers. All papers reflecting the periods of each database were considered. randomized-controlled trials (RCT), cross-sectional studies, retrospective and prospective cohort studies, and comparative studies were prioritized.

Papers were excluded that did not address neuropathic pain after TKR specifically. Case reports, conference abstracts, study protocols, review articles, and foreign language papers where obtaining an English translation was difficult were also excluded. Systematic reviews and meta-analyses were collected to review their included papers.

Studies investigating treatment for post-TKR neuropathic pain (e.g. perioperative pregabalin, 5% lidocaine plasters, perioperative nefopam or ketamine) were considered. Other treatments like desensitization techniques, specific medicinal applications, nerve blocks or surgical managements (e.g. release of a trapped nerve/relocation or other neuroma management) were also included.

After the search, undertaken by an experienced clinical librarian (Divall P) and meeting search requirements (Supplementary material), the titles and/or abstracts of these papers were independently screened by three reviewers to identify studies that met inclusion criteria. Papers were excluded if they had irrelevant titles or only had abstracts, did not mention neuropathic pain, did not meet our inclusion criteria, or met exclusion criteria. Full versions of eligible papers were obtained and independently reviewed by three reviewers to confirm eligibility. Disagreements between reviewers were resolved through full team discussion.

A preferred reporting Items for systematic reviews and meta-analyses (Preferred Reporting Items for Systematic Reviews and Meta-analyses)[11] flowchart was created to represent the screening and selection process. To assess quality three reviewers independently scored each selected study against pre-defined modified Coleman criteria[12]. Coleman A helped stratify studies and narrow down to higher quality papers. Coleman B sought answers to specific review outcomes to identify studies with data. Selection was confirmed by study group consensus.

Bias was assessed using risk of bias 2.0[13] for RCT and risk of bias in non-randomized studies of Interventions-I[14] for non-RCT studies. These assess bias across domains including methods, patient allocation, blinding, reporting bias and others. The bias assessments were discussed in a team meeting. Differences between reviewers were resolved through group discussion. A traffic-light diagram was constructed to summarize bias assessments.

Statistical analysis

Data was extracted from each study to define study numbers, population studied, interventions, duration of follow-up, attrition and outcomes assessed. Data was extracted from figures for one study[15] using standard techniques[16] and converted data [e.g. pain Visual Analogue Scale (VAS)] using recommended methods to permit comparisons[17]. The Knee Injury and Osteoarthritis Outcome Score pain scale reported in one study[18] required change in direction to match the VAS scale. The analysis plan was defined in the registered protocol dependent on the data extracted. The review team met frequently to discuss conflicts, review quality, bias, data extracted and agree actions through the review process.

RESULTS

The literature review identified 9146 studies based on our search strategy which was kept broad. After removal of 2121 duplicates, studies had their abstracts reviewed focusing on treatment of neuropathic pain post-TKR. 38 met inclusion and exclusion criteria, full papers were obtained and reviewed by three reviewers and 31 papers were excluded.

The Preferred Reporting Items for Systematic Reviews and Meta-analyses flowchart (Figure 1) demonstrates this[11]. The final seven papers included two RCTs, three comparative observational studies, and two single arm studies. Characteristics of randomized studies and non-randomized studies (Table 1) are presented. Available data and its’ limitations precluded metanalysis. The synthesis without meta-analysis reporting guidelines were followed[19].

Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-analyses flow diagram. The Bertram et al’s paper[33] relating to the steroidogenic acute regulatory protein pathway was excluded from our review as it did not relate specifically to neuropathic pain post total knee replacement. While it did use Neuropathic Pain Scores such as Douleur-Neuropathique-4 and PainDETECT, the data that was collected only included mean values and was not used to classify or delineate patients with neuropathic pain within their cohort. The change in PainDETECT scores was similar and did not change between one and four years. Their study did not show a significant difference in the mean PainDETECT scores during follow up. Chapman et al[27] was excluded as it related to primarily nociceptive pain and was not specific to post-total knee replacement. TKR: Total knee replacement; OA: Osteoarthritis.

Table 1 Summary of study designs for included studies.

No.	Ref.	Year	Study type	Intervention	Control	Follow-up (months)	Outcome	Conclusion
1	Rienstra et al[18]	2021	RCT	Duloxetine peri-operative	Analgesics, NSAIDs but no neuropathic medication	12	Pain severity using KOOS pain scale and VAS, and neuropathic pain using PainDETECT at 6 weeks, 6 and 12 months after TKR	Perioperative treatment with Duloxetine did not influence chronic or neuropathic pain up to one year after TKR
2	Buvanendran et al[25]	2010	RCT	Pregabalin peri-operative	Placebo tablets	6	Pain severity using immediate post-operative NRS, and proportion with neuropathic pain using S-LANSS at 3 and 6 months	Perioperative pregabalin treatment significantly reduced the rate of neuropathic pain to 6 months
3	Albayrak et al[23]	2017	Retrospective comparative	DRG RF Ablation	Analgesics, NSAID, local treatments	8	Pain severity using VAS, and neuropathic pain using DN4 at 15 days, 1 month and 8 months after 14-day admission for treatment of chronic and neuropathic pain three years after TKR	Radiofrequency ablation of the DRG at L4 improved the proportion of patients with neuropathic pain
4	Kretzschmar[15]	2019	Observational	DRG RF stimulator	NA	36	Pain severity using VAS, in patients selected for neuropathic pain using PainDETECT	Radiofrequency stimulation of DRG at L3&4 improved neuropathic pain to 1 year and this was sustained to three years
5	Yang et al[22]	2022	Retrospective comparative	Neurectomy, interventional pain procedures	Unclear-assume Analgesics NSAIDs	2	Pain severity using VAS, did not use a neuropathic pain score, but selected based on clinical examination	Selective denervation improves neuropathic pain after TKR
6	Zhong et al[21]	2018	Retrospective comparative	Neurectomy	Analgesics, NSAID, local treatments	12	Pain severity using VAS, did not use a neuropathic pain score. Ruled out other causes of persistent post-operative knee pain	Selective denervation for those that show response to local injection improves neuropathic pain after knee surgery
7	Clendenen et al[20]	2015	Observational	Hydro-dissection of nerve	NA	9	Pain severity using VAS, did not use a neuropathic pain score. Selected patients based on clinical examination	Hydro-dissection with steroid and local anesthetic to potentially free a stuck nerve improved chronic medial knee pain after TKR

RCT: Randomized-controlled trials; DRG: Dorsal root ganglion; RF: Radiofrequency; RF: Radiofrequency; NSAID: Nonsteroidal anti-inflammatory drug; KOOS: Knee Injury and Osteoarthritis Outcome Score; S-LANSS: Self-reported Leeds Assessment of Neuropathic Symptoms and Signs; DN4: Douleur-Neuropathique-4; TKR: Total knee replacement; NRS: Numerical Rating Scale.

Quality and risk of bias assessment (Tables 2, 3 and 4) found two of the seven papers reviewed were of good quality and low bias. Both were prospective RCTs investigating peri-operative medication to reduce post-surgical neuropathic pain. The retrospective comparative studies were of lower quality and with significant confounding leading to the bias assessment being severe or critical. The detailed evaluation of quality and bias and narrative explanation is given in the supplementary documentation (Supplementary material).

Table 2 Summary of quality and bias assessments for included papers.

No.	Ref.	Year	Quality: Coleman A	Quality: Coleman B	Bias	Bias method
1	Rienstra et al[18]	2021	95.0	79.1	Low	ROB2
2	Buvanendran et al[25]	2010	91.7	79.1	Low	ROB2
3	Albayrak et al[23]	2017	43.3	48.8	High	ROBINS
4	Kretzschmar[15]	2019	33.3	30.2	High	Single arm used ROBINS
5	Yang et al[22]	2022	16.7	0.0	High	ROBINS
6	Zhong et al[21]	2018	45.0	53.5	High	ROBINS
7	Clendenen et al[20]	2015	40.0	65.1	High	Single arm used ROBINS

ROB: Risk of bias; ROBINS: Risk of bias in non-randomized studies of intervention.

Table 3 Summary of risk of bias assessments for included papers.

ROB2	Ref.	Year	Randomization	Deviations	Outcome	Measurement	Reported result	Overall
1	Rienstra et al[18]	2021	Moderate risk	Moderate risk	Low risk	Low risk	Low risk	Low risk
2	Buvanendran et al[25]	2010	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk

ROB: Risk of bias.

Table 4 Summary of risk of bias in non-randomized studies of intervention assessments for included papers.

ROBINS	Ref.	Year	Confounding	Selection	Interventions	Deviation	Missing	Outcome	Reporting	Overall
3	Albayrak et al[23]	2017	Serious risk	Low risk	Moderate risk	Low risk	Serious risk	Moderate risk	Low risk	Serious risk
4	Kretzschmar[15]	2019	Serious risk				Low risk	Low risk	Low risk	Serious risk
5	Yang et al[22]	2022	Serious risk	Low risk	Moderate risk	Moderate risk	Moderate risk	Moderate risk	Low risk	Serious risk
6	Zhong et al[21]	2018	Serious risk	Low risk	Moderate risk	Low risk	Moderate risk	Moderate risk	Low risk	Serious risk
7	Clendenen et al[20]	2015	Serious risk				Low risk	Moderate risk	Low risk	Serious risk

ROBINS: Risk of bias in non-randomized studies of intervention.

Three papers addressed interventions on the peripheral sensory nerve. Clendenen et al[20] reported on 16 patients with chronic medial knee pain after TKR who had hydro-dissection (with 5 mL of ropivacaine and 20 mg of methyl-prednisolone) of the infra-patellar branch of the sural nerve under ultrasound imaging. The VAS improved from 8.2 before treatment to 2 at final follow-up around 9 months later although two patients needed revision TKR.

Zhong et al[21] reported on the benefits of selective peripheral nerve resection/resisting for chronic pain in 22 self-selected patients after TKR and compared these retrospectively to 38 patients who did not have nerve surgery. They observed VAS improved from 6.7 to 1.2 at one year in the operated group and from 6.4 to 4.1 in those not having surgery.

Yang et al[22] reported on 55 patients with chronic pain still present around 22 months after knee procedures (42, 76.4% had TKR) comparing outcomes in 37 who had pain relief following a nerve block of which 24 had neurectomy to 18 who did not respond to the local injection, and none had neurectomy. Pain VAS improved from 6.5 to 0.9 after intervention compared to 6.1 to 5 in the control group.

Two studies investigated modifying the dorsal root ganglia (DRG). The response to pulsed radiofrequency ablation of the 4^th lumbar dorsal root ganglion[23] in 22 patients with ongoing chronic pain three years after TKR compared to 17 who had standard treatment including transcutaneous electrical nerve stimulation, exercise, and pain medication as inpatients for 14 days. This study reported pain severity (VAS) and proportion with neuropathic pain (DN4) and suggested that ablation of one lumbar dorsal root ganglion (DRG) reduced pain at one month and at the follow-up at 253 ± 109 days.

VAS for pain on activity improved from 5.9 to 4.4 in the control group and from 6.6 to 3.5 in the intervention group. No difference was observed in pain at night or rest. The proportion reporting neuropathic pain reduced from 65% to 59 % in the control group and from 68% to 0% in the intervention group. The reasons why pulsed radio-frequency ablation of only the L4 DRG gives pain relief that is sustained for eight months was not discussed. The observation of difference in pain relief on activity and at rest needs explanation.

Kretzschmar[15] used DRG stimulators at lumbar 3 and 4 foramens in 9 patients with chronic pain post-TKR and assessed change using VAS to 36 months showing sustained improvement from 5.8 at baseline to < 2 at 1 year. This remained unchanged to three years.

Finally, two studies addressed modifying central sensitization[24] (amplified neural signaling causing hypersensitivity), in the peri-operative period. Buvanendran et al[25] investigated, in a placebo-controlled double-blind RCT, whether perioperative oral pregabalin influenced chronic pain after TKR in 240 patients. The numeric rating scale changed from 7.7 to 5.2 in the intervention group and 8 to 6.1 in the control group. They concluded that perioperative pregabalin reduced the proportion with neuropathic pain based on the S-LANSS a month after surgery and at 3 and 6 months (0% vs 5.2%) but risked causing sedation and confusion. This study is one of two that reported the proportion of patients with neuropathic pain and so is difficult to compare with other papers.

Rienstra et al[18] investigated the effect of pre-operative Duloxetine to modify the capacity for central sensitization on chronic and neuropathic pain in a RCT on patients having TKR (n = 61) or total hip replacement (n = 50). Outcomes were pain severity (VAS, Knee Injury and Osteoarthritis Outcome Score) and neuropathic pain (PainDETECT) at 6 weeks, 6 months and 12 months and observed no difference between groups at these timepoints. For the 61 TKR patients VAS changed in the intervention group from 5.3 to 2.5 and in the control group from 6.6 to 2.4. at 12 months. Although the paper used PainDETECT, only scores were reported rather than proportion of patients having neuropathic pain.

Tables 5, 6 and 7 show that the VAS mean difference ranged from 0.1 to 4.1 after treatments where the absolute minimum clinically important difference for VAS after TKR is 2[26]. Figure 2 shows the wide range in the VAS Hedge’s G standardized mean difference (SMD).

Figure 2 Forest plot. A: Calculated the standardized mean difference of pain Visual Analogue Scale as reported between 6 months and 12 months after intervention. One randomized controlled trial and three retrospective studies are assessed. We have not meta-analyzed this data. Two studies report no effect, or very small effects of the intervention investigated. Two studies report good effects, but these were of poorer quality and had significant bias. For two single arm studies (Kretzschmar[15], Clendenen et al[20]), we calculated the mean difference in Visual Analogue Scale using the highest and lowest values for the control arm in other studies to provide a possible range of mean difference; B: Demonstrates the log odds ratio of patients with and without neuropathic pain after total knee replacement. The first study reports a clear effect of peri-operative oral pregabalin postulating a lasting effect on central sensitization, while the second is a comparative study of pulsed radiofrequency (radio-frequency) dorsal root ganglion ablation for neuropathic pain also reporting a sustained and substantial effect. CI: Confidence interval; REML: Residual maximum likelihood.

Table 5 Data from publications - baseline Visual Analogue Scale pain.

No.	Ref.	Year	Recruitedn I	Recruitedn C	VAS baseline I	VAS baseline I_SD	VAS baseline C	VAS baseline C_SD
1	Rienstra et al[18]	2021	31	29	5.3	2	6.6	1.9
2	Buvanendran et al[25]	2010	120	120	7.7	1.9	8	1.3
3	Albayrak et al[23]	2017	22	17	4.3	1.7	5	2.4
4	Kretzschmar[15]	2019	9	0	5.9	1.5
5	Yang et al[22]	2022	37	18	6.5	1.9	6.1	1.8
6	Zhong et al[21]	2018	22	38	6.7	1.4	6.4	2
7	Clendenen et al[20]	2015	16	0	8	1

Table 5 gives the number and the extracted pain Visual Analogue Scale at baseline noting pain severity in the intervention and control/comparator arms with the SD. The first paper used the Knee Injury and Osteoarthritis Outcome Score pain scale which required reversing the direction and division by 10 to make it comparable to the Visual Analogue Scale. Data was extracted from a figure for the Kretzschmar’s study[15]. I: Intervention; C: Control/comparator; VAS: Visual Analogue Scale.

Table 6 Data from publications - change in pain: Follow-up pain Visual Analogue Scale and difference from baseline.

No.	Ref.	Year	FU number I	FU number C	VAS FU I	VAS FUI_SD	VAS FU C	VAS FU C_SD	VAS MD	VAS CI MD	VAS SMD	VAS CI SMD
1	Rienstra et al[18]	2021	20	28	2.5	1.6	2.4	1.9	0.1	-0.9 to 1.1	0.055	-0.51 to 0.62
2	Buvanendran et al[25]	2010	113	115
3	Albayrak et al[23]	2017	22	17	2	1.6	2.8	2.1	-0.8	-2.0 to 0.4	-0.428	-1.06 to 0.20
4	Kretzschmar[15]	2019	9	0	1.8	0.4			-3.2 to -0.6		-0.42 to -2.47
5	Yang et al[22]	2022	37	18	0.9	1.2	5	1.7	-4.1	-4.9 to -3.3	-2.93	-3.71 to -2.15
6	Zhong et al[21]	2018	22	38	1.2	0.3	4.1	1.4	-2.9	-3.4 to -2.3	-2.53	-3.22 to -1.84
7	Clendenen et al[20]	2015	16	0	2	2.8			-3.0 to -0.4		-0.16 to -1.26

Table 6 gives the number and the extracted pain Visual Analogue Scale (VAS) at follow-up between 6 months and 12 months after intervention noting pain severity in the intervention and control/comparator arms with the SD. The first paper used the Knee Injury and Osteoarthritis Outcome Score pain scale which required reversing the direction and division by 10 to make it comparable to the VAS scale. Data was extracted from a figure for the Kretzschmar[15] study. The MD and the 95% confidence interval are given for comparative studies to allow easy reference to the VAS minimum clinically important difference of 2. The SMD is calculated (Hedges g, as some samples were quite small) along with the 95% confidence interval. For the single arm studies, we calculated the MD/SMD using the highest and lowest values for the control arm in other studies to provide a possible range of MD and SMD. FU: Follow-up; I: Intervention; n: Number; C: Control/comparator; VAS: Visual Analogue Scale; CI: Confidence interval.

Table 7 Data from publications - log odds ratio of numbers with neuropathic pain in each trail arm.

No.	Ref.	Year	FU number I	FU number C	Final_NP number _I	Final_nonNP number _I	Final_NP number _C	Final_nonNP number _C	Log odds ratio	CI Log odds ratio	Lower 95%CI	Upper 95%CI
1	Buvanendran et al[25]	2010	113	115	0	113	6	109	-2.6	-5.5 to 0.3	-5.5	0.3
2	Albayrak et al[23]	2017	22	17	0	22	10	7	-4.1	-7.1 to -1.2	-7.1	-1.2

Two papers presented data on final proportions of patients with neuropathic pain in the intervention and control arms so log odds ratio and its 95% confidence interval could be assessed. FU: Follow-up; I: Intervention; C: Control/comparator; NP: Neuropathic pain; CI: Confidence interval.

DISCUSSION

A significant proportion of patients having TKR continue to have pain post-TKR including nociceptive[27] and neuropathic pain. Neuropathic pain was identified based on symptoms patients reported and/or the signs clinicians elicited. Three neuropathic pain questionnaires (DN4, Identification Pain questionnaire, and S-LANSS) are only screening tools. These cannot assess severity but can document change in proportions with neuropathic pain. PainDETECT also provides a severity score (Supplementary material).

The severity of neuropathic pain was obtained using patient grading of pain in few studies with most reporting a pain scale, usually a VAS. The proportion of patients with neuropathic pain after TKR was not usually provided. Only two studies reported the change in the proportion of neuropathic pain over time. We were unable to collect enough information on proportions to extract a direction of effect. Although PainDETECT questionnaire was used in one paper[18], only the score was reported at each time-point rather than the proportion considered “neuropathic”.

Studies did not advise how surgeons could reduce the rate or severity of neuropathic pain after TKR. Neuropathic pain is probably initiated by the surgical impact on medial parapatellar nerves supplying sensation to the medial side of the knee. The superior, middle and inferior genicular nerves[28,29] are at risk of injury during the TKR.

Some branches must be divided to access the arthritic knee as the patella is dislocated laterally to expose the tibio-femoral joints. These nerves may also be trapped by sutures when repairing the extensor mechanism and the post-surgical scar could trap a sensory nerve or tether it[30,31]. The literature does not provide clear advice on how surgeons should address the cut parapatellar nerves. The common options for identified cut nerves include: (1) Ignore the cut nerve; (2) Repair it hoping to reduce neuropathic pain incidence and improve hypoesthesia; (3) Relocate the cut nerve end probably in the vastus medialis muscle; and (4) Be aware of the location of the branches and take care not to include the nerve in the extensor mechanism sutures[30,31].

This review has identified four main approaches to the management of established neuropathic pain but the evidence for each is currently equivocal.

The perioperative medication with Pregabalin or Duloxetine intends to modify central sensitization to pain and to reduce the severity of pain. This attempts to prevent neuropathic pain but risks exposing the majority who would not get neuropathic pain to drug adverse effects. The two studies were RCTs providing the best quality evidence. However, extracting data of proportion with neuropathic pain was not possible in one, the other did not measure pain severity. One suggested that perioperative pregabalin reduced the rate of neuropathic pain, but the second found no difference between those treated with duloxetine and the control group.

The second pathway is use of local techniques such as desensitization, or capsaicin patches which are not well researched for post-TKR neuropathic pain. Image guided hydro-dissection using local anesthetic and steroid reduced neuropathic pain in a single arm study and the sensitivity analysis of possible VAS SMD suggests that this method would merit further investigation to establish if absolute SMD of pain-VAS is ≥ 2[26].

The third pathway is to identify the single patellar nerve that is the cause or the main pathway of pain transmission. Neurectomy (using radiofrequency, cryoablation or surgery) and resisting of the cut nerve in muscle can either address the trigger for neuropathic pain or disrupt the pain pathway. Two studies investigated this. In both there were comparative groups which were not offered the same intervention and patients chose the treatment. Both report an effect favoring surgery and the lower 95% confidence interval was greater than the absolute minimum clinically important difference of around 2 on a VAS[26] indicating a possibly useful effect. Both were low quality papers with significant bias, so the effectiveness and harms are unproven. The timing of intervention and whether it should be considered after failure of simpler measures needs high quality investigation. Denervation of an undamaged nerve could impair joint proprioception.

Finally, the proximal pain sensory pathway can be disrupted at the lumbar 3/4 DRG by either a stimulator or radio-frequency nerve ablation. The control group in the DRG ablation study was not comparable to the intervention group and the VAS SMD was below 2-points. The single-arm study using an implanted DRG stimulator demonstrated sustained pain reduction. The sensitivity analysis of the SMD assuming the highest and lowest VAS from other studies control groups hinted the possibility of a useful effect so this intervention would bear investigation. Our study demonstrates that the literature on the effectiveness of treatments of neuropathic pain post-TKR is poor.

However, we note that the STAR pathway of identifying pain causes post-TKR[32], including neuropathic pain, management signposting using appropriate drugs by general practitioners or referral to pain-management services improved pain outcomes to 1 year and some degree of pain relief was maintained to four years[33].

There are many causes of pain post-TKR (e.g. patellofemoral joint pain, neuropathic pain and non-specific aching) which can be identified on history and examination. Certain symptoms (e.g. neuralgia, allodynia, hyperalgesia or provoked pain) suggest neuropathic pain and distinguishes it from other nociceptive causes of post-TKR pain.

Increasingly we are becoming aware that the different symptoms of neuropathic pain have specific pathophysiology. Electrophysiology helps investigate this[34]. Research also indicates that different neuropathic pain symptoms respond to different treatments.

The potential objectives of the management pathway are shown in Figure 3. Based on the severity of neuropathic pain a possible treatment pathway is illustrated in Figure 4. However, every step of this pathway requires good quality studies; from establishing the cut-points of the pain-VAS to trigger a path, to the various interventions to establish effectiveness, time-to-resolution, and harms. This will provide information on how to appropriately advise the substantial numbers of patients with neuropathic pain after TKR of their treatment options. As consensus evolves on the interpretation and classification of neurophysiology findings in post-TKR neuropathic pain, this could be incorporated into the treatment pathway.

Figure 3 This shows the potential steps in the management pathway for prevention, diagnosis, assessment, and treatment of neuropathic pain after total knee replacement. At present each of these are not well and consistently investigated. The awareness in surgical teams is low as the focus remains on the implants and their survival. Clinicians usually do not offer patients specific post-total knee replacement neuropathic pain management, using generic post-surgical pain management instead. Clinically significant improvement is deemed as relative improvement of 30% of baseline or absolute reduction in Visual Analogue Scale of at least 2[1,25]. VAS: Visual Analogue Scale; MDC: Minimal detectable change.

Figure 4 This outlines a potential treatment pathway for neuropathic pain after total knee replacement. We consider that neuropathic pain needs identification, calibration, and management at three months after total knee replacement (TKR). Many of these interventions have good evidence base but not for neuropathic pain after TKR. For severe pain (Visual Analogue Scale > 7) the first step is to identify a possible cause using an ultrasound guided injection of local anesthetic. In those with 50% improvement of pain and in who simple hydro-dissection does not give lasting improvement consider neurectomy using radiofrequency or cryo-ablation or surgery to recite or release the nerve. If these measures fail, consider proximal methods such as dorsal root ganglion stimulation. As consensus evolves on the use and interpretation of neurophysiology to help classify severity of post TKR neuropathic pain, it could be incorporated into the treatment pathway as it may suggest an optimal treatment[34]. TKR: Total knee replacement; VAS: Visual Analogue Scale; S-LANSS: Self-reported Leeds Assessment of Neuropathic Symptoms and Signs; DN4: Douleur-Neuropathique-4; ID-Pain: Identification Pain questionnaire; TENS: Transcutaneous electrical nerve stimulation; USS: Ultrasound Scan; LA: Local anaesthetic; DRG: Dorsal root ganglion.

There were very few studies that met our criteria, different questionnaires were used to identify neuropathic pain post-TKR. The different treatments were tested at different time-points. The variation of interventions used, outcome measures assessing benefit, and timing of outcome meant that these studies were so heterogenous that even if there had been sufficient studies anything other than a narrative synthesis would be challenging.

CONCLUSION

Most reported studies classify neuropathic pain on symptoms and signs as “probable” or “definite” using questionnaires. Severity of neuropathic pain is reported using VAS, with PainDETECT also providing severity grading. Reported outcomes rarely include both the proportion classified as having neuropathic pain at each time-point and neuropathic pain severity. The quality of published evidence does not support making clear treatment recommendations for the sizeable number of patients experiencing neuropathic pain post-TKR. A possible logical pathway based on the current literature is outlined, but every step needs good quality evidence.

ACKNOWLEDGEMENTS

We acknowledge the contributions many clinicians who gave their clinical insights and helped steer interpretation, discussed various attributes of this study and helped us define the inclusion and exclusion criteria. Dr. Sadiq Bhayani, Consultant in pain management, contributed advice and guidance in the initial planning phases.