# Advances and challenges in neuropathic pain: a narrative review and future directions

Nadine Attal, Didier Bouhassira, Lesley A. Colvin

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## To cite this version:

Nadine Attal, Didier Bouhassira, Lesley A. Colvin. Advances and challenges in neuropathic pain: a narrative review and future directions. British Journal of Anaesthesia, 2023, 131 (1), pp.79-92. 10.1016/j.bja.2023.04.021. hal-04191628

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Submitted on 22 May 2025

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# Advances and challenges in neuropathic pain: a narrative review and future directions

Nadine Attal¹,*, Didier Bouhassira¹ and Lesley Colvin²

¹Inserm U987, UVSQ-Paris-Saclay University, Ambroise Pare Hospital, Boulogne-Billancourt, France and ²University of Dundee, Ninewells Medical School, Ninewells Hospital, Dundee, UK

*Corresponding author. E-mail: nadine.attal@aphp.fr

## Summary

Over the past few decades, substantial advances have been made in neuropathic pain clinical research. An updated definition and classification have been agreed. Validated questionnaires have improved the detection and assessment of acute and chronic neuropathic pain; and newer neuropathic pain syndromes associated with COVID-19 have been described. The management of neuropathic pain has moved from empirical to evidence-based medicine. However, appropriately targeting current medications and the successful clinical development of drugs acting on new targets remain challenging. Innovative approaches to improving therapeutic strategies are required. These mainly encompass rational combination therapy, drug repurposing, non-pharmacological approaches (such as neurostimulation techniques), and personalised therapeutic management. This narrative review reports historical and current perspectives regarding the definitions, classification, assessment, and management of neuropathic pain and explores potential avenues for future research.

**Keywords:** chronic pain; COVID-19; neuropathic pain; neurostimulation; pharmacotherapy; recommendations; screening questionnaires

## Editor's key points

* Over the past few decades there have been considerable advances in the assessment and management of neuropathic pain. This narrative review summarise historical aspects and provides a review of its classification and current management.

* Development of drugs acting on new targets has not been as successful as expected, but the repurposing of older drugs and development of newer treatment modalities, such as brain neuromodulation techniques, have contributed to reduce therapeutic failures. Individualised pain therapy remains the ultimate goal of therapy.

Neuropathic pain is one of the most incapacitating pains and represents a significant unmet medical need.¹ It may be caused by a large variety of conditions, including painful neuropathies (diabetic or non-diabetic), nerve lesions (mainly attributable to surgery or trauma), herpes zoster, discal her- niation, multiple sclerosis, spinal cord injury, head trauma, or stroke.¹ Over the past decades, the number of clinical studies devoted to neuropathic pain has dramatically increased. A newer definition and classification, now endorsed by the WHO, have appeared, and easy-to-use questionnaires have improved the detection and assessment of neuropathic pain. The management of neuropathic pain remains challenging despite the development of drugs acting on new targets, and innovative therapeutic strategies are required.

In this narrative review, we present brief historical and current perspectives regarding the definition, classification,
assessment, and management of neuropathic pain, with emphasis on pharmacotherapy and neurostimulation techniques (see Colloca and colleagues¹ and Moisset and colleagues² for reviews of other medical approaches), and explore potential avenues for future research. This will include recently recognised syndromes, such as acute neuropathic pain and COVID-19-related neuropathic pain. We will not discuss idiopathic trigeminal neuralgia, which necessitates distinct management,³ or detail the pathophysiology of neuropathic pain⁴ or paraclinical investigations (neurophysiological techniques, skin punch biopsy, neuroimaging, and genetics).⁵

## Brief history of neuropathic pain

The idea that pain could be caused by a nerve lesion was first proposed by the medieval medical scholars Rhazes, Haly Abbas, Avicenna, and Jorjani in the 10th to 11th century.⁶ They named this type of pain ‘vaja al asab’ (nerve-originated pain). Whilst Rhazes described the properties of nerve-originated pain, Haly Abbas described its quality (numbness, tingling, and needle-like); Avicenna classified its causes into the brain, spinal cord, and peripheral nerve, and noted the coincidence with stroke. Finally, Jorjani introduced the concept of traumatic nerve pain and reported that nerve injury was more painful than other tissue injuries because of connections between nerves and brain. He also considered sciatica as a nerve-originated pain.

More modern concepts and terminologies for nerve injury pain appeared in the 18th century.⁷ In 1773, John Fothergill described trigeminal neuralgia to the Medical Society of London, whilst the term itself (neuralgia) was first proposed in 1801 in French ('névralgie') to indicate 'an affection of one or more nerves causing pain, which is usually of an intermittent but frequently intense character'. (It is still used for trigeminal, occipital, pudendal, or postherpetic neuralgia.⁸) In 1892, the surgeon Silas Weir Mitchell described the painful post-traumatic nerve lesions associated with vasomotor and sudomotor changes encountered during the American Civil War, which he named 'causalgia' (now called 'complex regional pain syndrome').⁹ He described these pains as 'aching, shooting, or burning (...) exquisitely hyperaesthetic so that a touch or tap of the finger increases the pain'. In 1906, the French neurologists Jules Dejerine and Gustave Roussy described pain associated with a thalamic stroke, now called 'post-stroke pain',¹⁰ and the British neurologists Henry Head and Gordon Holmes¹¹ published in Brain in 1911 the sensory consequences, including pain, of cerebral lesions at different sites. In 1924, the American neurologist A. H. Gordon¹² introduced the word 'neuropathy' in an article entitled, 'Clinical Lecture on Lead Neuropathy'. Since then and up to the 1980s, these terms, and the words 'neuritis', 'deafferentation pain', or 'neurogenic pain', have been commonly used to qualify pain associated with a nerve lesion.

In 1988, Bennett and Xie¹³ developed the first animal model of 'neuropathic pain' created by chronic constriction injury of the sciatic nerve in the rat. This was followed by a dramatic increase in the development of animal models of neuropathies.¹⁴,¹⁵ A decade later, in 1998, the two first large-scale multicentre RCTs of drug therapy (gabapentin) in neuropathic pain (painful diabetic neuropathies and postherpetic neuralgia) were published in JAMA.¹⁶,¹⁷ This marked the beginning of the modern age for neuropathic pain and was followed by an exponential increase of preclinical and clinical

research, as illustrated by the citation rate for neuropathic pain, which rose from 529 per year in 1998 to more than 3000 per year since 2019 (3256 in 2022).

## Definition and classification

### Chronic neuropathic pain

In 1994, the International Association for the Study of Pain (IASP) proposed the first official definition of neuropathic pain ('pain initiated or caused by a primary lesion or dysfunction of the nervous system'). This definition was first modified in 2008¹⁸ ('pain arising as a direct consequence of a lesion or disease affecting the somatosensory system'). Since 2011, neuropathic pain has been officially defined as 'pain caused by a lesion or disease of the somatosensory system'.¹⁹ In particular, the word 'dysfunction' is now absent from the definition because many chronic pain conditions are related to CNS dysfunction without evidence for a nerve lesion or tissue injury. These conditions, which include in particular fibromyalgia, complex regional pain syndrome, and irritable bowel disease, are now referred to as a third pain type called 'noci-plastic pain'.²⁰,²¹ Although the benefit of stringent criteria to define neuropathic also raises several issues,²² this new definition has the merit of standardisation for clinical research²³ and is now fully endorsed by the medical and scientific community.

In 2017, the IASP proposed a new classification for chronic pains,²⁴ including neuropathic pain,²⁵ which is now incorporated into the International Classification of Diseases and Related Health Problems (ICD-11) of the WHO.²⁶ The neuropathic pain classification differentiates pain of peripheral and central origin and includes nine conditions, such as painful neuropathies, postherpetic neuralgia, painful nerve lesion, or spinal cord injury pain (Fig. 1).²⁵ Each condition is part of more detailed content models, which describe investigations supporting a definite diagnosis and contain codes for pain severity, temporal characteristics, and psychosocial factors. This is the first comprehensive internationally accepted classification, representing a large step forward that may contribute to enhanced reporting and improved treatment of neuropathic pain.

### Acute neuropathic pain

To meet the current definition of neuropathic pain, there is no requirement for chronicity, although it is often assumed. The definition of neuropathic pain was updated to reflect that this pain may occur acutely.¹⁹ Acknowledging the challenges of diagnosing acute neuropathic pain, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks has produced guidance for diagnostic criteria for acute neuropathic pain through expert opinion and literature review.²⁷ Examples of acute neuropathic pain (often associated with inflammatory pain) include common conditions, such as post-surgical pain, where a nerve lesion may result from the type/site of surgery, acute sciatica, or acute herpes zoster, and rare conditions, such as Guillain-Barré syndrome. Furthermore, up to 70% of people exposed to neurotoxic chemotherapy, such as oxaliplatin or cisplatin, may have acute chemotherapy-induced peripheral neuropathy (CIPN), sometimes requiring dose reduction or cessation of chemotherapy (with implications for survival),²⁸ and around a third are left with persistent CIPN.²⁹ The severity of acute
<figure><img src="image_3.png" /><figcaption>Fig 1. Classification of neuropathic pain (NP) conditions by the International Association for the Study of Pain. This classification is now part of the *International Classification of Diseases* 11th Edition.<sup>25</sup></figcaption></figure>

neuropathic pain may be linked to nociceptive fibre dysfunction, as in Guillain-Barré syndrome,³⁰ and acute neuropathic pain may predict chronic pain after surgery or herpes zoster.³¹⁻³³ Detecting and managing acute neuropathic pain are important not only to alleviate suffering but also allow targeted management (e.g. regional anaesthesia) in vulnerable individuals.³⁴ Preventing acute neuropathic pain is now possible as regards herpes zoster with recombinant zoster vaccines and zoster vaccines live, which dramatically reduce the risk of acute herpes zoster and postherpetic neuralgia.³⁵,³⁶

## COVID-19 and neuropathic pain: a new entity?

Early in the COVID-19 pandemic, neurological manifestations of acute COVID-19 were described, including seizures, strokes, or encephalitis, in addition to the now well-recognised anosmia and ageusia.³⁷,³⁸ Pain is also a well-acknowledged symptom particularly at the acute phase, affecting around 70% of COVID-19 infected people (including mild-to-moderate cases), often consisting of myalgia and headache.³⁷⁻⁴¹ However, neuropathic pain may also be a concern.⁴²⁻⁴⁴ A retrospective analysis of post-ICU patients after COVID-19 infection found that 94% had pain at discharge, whilst 23.5% were suspected of neuropathic pain, with lower levels after receiving ketamine as part of their sedation regime.⁴⁵ The mechanisms of neuropathic pain in severe COVID-19 include generalised CNS inflammation and direct neuronal damage through neuroinvasion.³⁸,⁴⁶ Neurones are known to express angiotensin-converting enzyme 2 (ACE2) receptors, potentially utilised by the SARS-CoV-2 virus as an entry point to neural cells. This

may negatively impact mitochondrial function, whilst there is a loss of neuroprotective and neuro-immunomodulatory effects regulated by ACE2.<sup>47,48</sup>

Long-term neurological sequelae of COVID-19 have also been described even in non-hospitalised people, including pain, migraine, and cognition disorders, but also more severe complications, such as stroke, peripheral nervous system disorders, seizures, extrapyramidal disorders, and encephalopathy.⁴⁹ New-onset chronic pain is more common after hospital discharge from COVID-19 (19.6%) than after discharge for other reasons (1.4%).⁴⁰ Long COVID, which refers to persistent changes after COVID-19 infection, may affect up to 20% of subjects⁵⁰ and often includes pain. Evidence for new-onset persisting neuropathic pain after COVID-19 has recently been documented.⁴⁴,⁵¹⁻⁵⁵ In studies using neuropathic pain screening questionnaires, new-onset neuropathic pain for at least 1 month was identified in 17–25% of patients hospitalised previously for COVID-19 infection.⁵¹⁻⁵³ A recent prospective study of 226 COVID-19 infected individuals found that 7.6% of those with new-onset chronic pain had clinical evidence for neuropathic pain.⁵⁴ Another large-scale prospective study of 1656 participants, including 524 COVID-19 infected patients and a control unexposed group, reported that COVID-19 infected patients had three times higher risk of peripheral neuropathy symptoms in the extremities within 3 months after their infection (after adjusting for history of chronic pain and neuropathy) and a higher risk of pain (24.2% vs 9.8%).⁵⁵

## Current diagnosis and clinical assessment of neuropathic pain

### Success story of diagnostic questionnaires

Neuropathic pain has clinical characteristics that differentiate it from other types of pain, in particular nociceptive pain.⁵⁶ These characteristics encompass several symptoms or sensory descriptors (e.g. burning, cold pain, electric shocks, tingling, pins and needles, numbness, and itch) and are common to diverse aetiological conditions (e.g. post-stroke pain and diabetic painful neuropathies).⁵⁷ Clinical examination shows hypoesthesia or hypoalgesia (decreased pain sensation) to several modalities (generally warm, cold, and pinprick, indicating impairment of small nociceptive fibres or spinothalamic pathways) in the painful area or allodynia, hyperalgesia, and vasomotor or sudomotor changes particularly after nerve trauma.¹

In 1975, Ronald Melzack⁵⁸ developed the widely used McGill Pain Questionnaire to assess various dimensions of pain. Although this questionnaire was not conceived specifically for neuropathic pain, it was subsequently found that several items could differentiate patients with and without neuropathic pain.⁵⁹ These studies opened the way to the development of several simple and easy-to-use diagnostic (or screening) questionnaires over the past two decades (Table 1), aiming to detect neuropathic pain in patients with multiple pain conditions.⁵⁶ The most commonly used are the Douleur Neuropathique en 4 questions, also called Douleur Neuropathique 4 questionnaire (DN4)⁷¹; PainDETECT⁷²; and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS).⁷³ DN4 and LANSS include a very short examination, but self-completed questionnaires (DN4 interview and S-LANSS) are also validated. They have up to 80% or 90% sensitivity and specificity and may be used by non-specialists or be self-
<table><caption>**Table 1** Examples of clinical results obtained with neuropathic pain questionnaires in clinical or therapeutic studies. CCR2, CC chemokine receptor 2; DN4, Douleur Neuropathique 4 questionnaire; NPSI, Neuropathic Pain Symptom Inventory.</caption><thead><tr><th>Questionnaire</th><th>Examples</th></tr></thead><tbody><tr><td>Neuropathic diagnostic</td><td></td></tr><tr><td>Detection of neuropathic pain in complex painful conditions</td><td>Show that up to 50% of post-surgical pain is neuropathic (DN4)<sup>60</sup></td></tr><tr><td>Epidemiological studies in the general population or after surgery</td><td>Prevalence of neuropathic pain in the general population estimated 5–10%<sup>56,61</sup>, prevalence of neuropathic pain (DN4) 6 months after surgery estimated 3.2% (laparotomic herniorrhaphy) to 37.1% (mastectomy)<sup>52</sup>, at 12 months, neuropathic pain identified in 35.4% and 57.1% of patients with moderate and severe chronic post-surgical pain, respectively<sup>63</sup></td></tr><tr><td>Cohort prospective studies</td><td>Higher DN4 score or positive response on the DN4 immediately after surgery associated with increased risk of neuropathic pain 2–3 months after surgery<sup>31,32</sup>, positive DN4 score in patients with acute herpes zoster associated with higher risk of postherpetic neuralgia at 12 months<sup>33</sup></td></tr><tr><td>Neuropathic specific assessment</td><td></td></tr><tr><td>Have shown that sensory phenotypes are not linked to the aetiology of neuropathic pain</td><td>Distinct clusters of patients linked to aetiology identified in patients with diabetic neuropathic pain or postherpetic neuralgia (PainDETECT)<sup>64</sup>; shared phenotypes (NPSI) across a large multi-aetiological group of patients with neuropathic pain<sup>57</sup></td></tr><tr><td>Have shown that several dimensions of neuropathic pain may be more sensitive to change than average pain intensity in clinical trials</td><td>Conventional (pregabalin) or newer drug therapies (CCR2 antagonists and Nav1.7 antagonists) failing on the primary outcome but significantly effective on neuropathic pain dimensions (NPSI)<sup>65–67</sup></td></tr><tr><td>Have suggested the relevance to stratify patients for clinical trials on the basis of sensory phenotypes</td><td>Exploratory analyses using NPSI at baseline in placebo-controlled RCTs showing enhanced response to oral oxcarbazepine in patients with burning and paroxysmal pain,<sup>68</sup> capsaicin high-concentration patches in patients with paroxysmal pain,<sup>69</sup> and botulinum toxin A in patients stratified into clusters «deep pain» and «evoked pain»<sup>70</sup></td></tr></tbody></table>

administered by patients.<sup>56,60</sup> These questionnaires share many descriptors, although they were developed independently in different countries and in patients with distinct languages, which confirms that pain qualities are universal and have a common biological basis. They have been translated and revalidated into more than 90 languages.<sup>56</sup> Their applications for routine and clinical research have been manifold<sup>56</sup> (Table 1). In particular, these questionnaires have contributed to provide an estimation of the prevalence of neuropathic pain in the general population<sup>61</sup> and in multiple settings, particularly after surgery.<sup>31,32,62,63</sup> Their use has largely expanded in the world, including in developing countries.<sup>56</sup> However, these questionnaires also have limitations: they fail to identify up to 20% of neuropathic pains depending on the context, their clinical examination is succinct or absent, they do not provide information about the neurological lesion, and they are difficult to apply for multiple pain areas.<sup>56</sup>

## Diagnostic algorithm

In 2008, the Neuropathic Pain Special Interest Group (NeuPSIG) of the IASP proposed a grading algorithm for the classification of neuropathic pain,<sup>18</sup> which was revised in 2016.<sup>19</sup> This grading system includes four criteria based on relevant history of nerve lesion, pain distribution in a neuroanatomical area, sensory signs in the neuroanatomical area, and diagnostic tests confirming a lesion or disease of the nervous system. This allows the characterisation into unlikely, possible, probable, or definite neuropathic pain depending on the number of criteria. The advantage of this algorithm is to propose a common language and classification of neuropathic pain syndromes particularly for research or clinical trials.<sup>19</sup> However, it is also subject to limitations because it is focused on the neurological lesion to the detriment of symptoms and has not

been fully validated.<sup>22</sup> Despite these limitations, this algorithm may be successfully combined with the use of diagnostic questionnaires to formally identify neuropathic pain, which is particularly useful for clinical research.<sup>56</sup>

## Questionnaires to assess neuropathic pain

Other than diagnostic questionnaires, self-assessment neuropathic questionnaires based on pain quality have been developed over the past 15 yr to quantify neuropathic symptoms.<sup>4</sup> The Neuropathic Pain Scale (NPS)<sup>74</sup> and Neuropathic Pain Symptom Inventory (NPSI),<sup>75</sup> translated and validated into multiple languages, are specific to neuropathic pain and are commonly used. The underlying concept for their development was that conventional measures of pain intensity (assessed by 0–10 numeric rating scale, where 0 is no pain and 10 is the maximal imaginable pain) are insufficient to capture the diversity of neuropathic pain symptoms in routine or clinical studies. Hence, these questionnaires are now largely used in clinical trials and may be more sensitive to treatment than conventional measures of pain intensity<sup>65–67</sup> or contribute to detect responder profiles to therapy (Table 1). Furthermore, the symptoms assessed with these questionnaires may be correlated to biomarkers of the neurological lesion,<sup>56</sup> suggesting a correspondence between symptoms and mechanisms.

## From empirical evidence to rational drug therapy in neuropathic pain

### From empirical discovery to elucidation of mechanisms

The gold standard for neuropathic pain treatment includes anti-epileptics and antidepressants, whose efficacy has been
discovered empirically. Diphenylhydantoin was the first drug reported to be effective in trigeminal neuralgia in 1942.⁷⁶ This was followed by carbamazepine in 1950, which remains the drug of choice for this condition,³ whilst its efficacy in other neuropathic pains is debatable.²,⁷⁷ The further elucidation of the mechanisms of action of these drugs, which primarily block voltage-gated sodium channels, has opened the way to the development of newer anti-epileptics with sodium channel-blocking properties (e.g. oxcarbazepine, lacosamide, and lamotrigine) or local anaesthetics, such as lidocaine 5% plasters for peripheral neuropathic pain.⁷⁷

Gabapentin and pregabalin represent a more recent class of anti-epileptics devoid of sodium channel-blocking properties. Gabapentin was initially developed as a GABAergic anti-epileptic. Its efficacy in neuropathic pain was initially reported in anecdotal cases then confirmed in large multicentre trials.¹⁶,¹⁷ A few years later, it was discovered that gabapentin does not act on gamma-aminobutyric acid receptors, but instead it modulates a pre-synaptic subunit of calcium channels at the spinal cord level (the alpha2delta subunit), leading to an inhibition of injury-induced spinal neuronal excitability. It may also act on the supraspinal modulation of affective qualities of pain.⁷⁸ Pregabalin, which has similar mechanisms of action, was launched in 2004 in USA. These drugs, which have become the gold standard for neuropathic pain, have inaugurated a new class of anti-epileptics, called the alpha2delta ligands. Newer alpha2delta ligands, such as mirogabalin, available in Japan, or newer gabapentin formulations (gabapentin extended release) have been subsequently developed.²,⁷⁷ However, these drugs also raise safety concerns so that careful risk/benefit assessment is required when prescribing.⁷⁹

In 1960, the analgesic efficacy of imipramine, a tricyclic antidepressant, was incidentally discovered by Paoli and colleagues⁸⁰ in patients with multiple sclerosis hospitalised for depression in Salpetrière Hospital (Paris, France). The authors observed that not only the depression of patients but also their neuropathic pain was relieved by the drug, which the authors published in *Revue Neurologique*.⁸⁰ Two to three decades later, in the 1980s and early 1990s, seminal works of Mitchell Max and colleagues⁸¹⁻⁸³ confirmed that the analgesic efficacy of antidepressants was independent on their effect on mood and probably involved central effects on brainstem descending inhibitory controls. Subsequent animal studies found that they also had a second delayed peripheral mechanism of action on beta-2 adrenergic receptors.⁸⁴ Antidepressants devoid of anticholinergic activity with better safety profile have been further developed, but only serotonin and noradrenaline re-uptake inhibitors (SNRIs), such as duloxetine, are effective, probably because their analgesic activity necessitates noradrenergic descending inhibitory controls.²,⁷⁷

Capsaicin, the pungent ingredient of chilli pepper, has been used for pain since ancient times, and low concentration creams were developed for postherpetic neuralgia in the 1980s.³⁵,⁸⁶ In 1997, David Julius and his team cloned the transient receptor potential vanilloid Type 1 (TRPV1) receptor, the target for capsaicin on nociceptive C fibres, which was acknowledged by the Nobel Prize for Medicine in 2021.⁸⁷ High-concentration capsaicin patches (8%) were developed subsequently and are approved for peripheral neuropathic pain.⁸⁸ It is now established that high-concentration capsaicin induces a long-term defunctionalisation of TRPV1 receptors, mediated by the ablation of TRPV1-expressing axon terminals induced by a calcium-dependent protease (calpain), which is followed

by the regeneration of afferent terminals.⁸⁹ This compound might also have disease-modifying effects.⁹⁰

## Evidence-based recommendations for neuropathic pain

Over the past decades, numerous evidence-based recommendations have appeared for multiple neuropathic pain conditions. Most initial recommendations focused on aetologically defined neuropathic pains, particularly diabetic painful neuropathies, postherpetic neuralgia, or spinal cord injury pains.⁸⁵,⁸⁶,⁹¹ However, recent meta-analyses have shown that drugs effective on one neuropathic condition had generally similar efficacy effective on another with few exceptions.⁷⁷,⁹² Furthermore, clinical studies have shown that most neuropathic conditions share clinical characteristics, suggesting common underlying mechanisms, without specific pattern pertaining to a single aetiology.⁵⁷ This further established the modern concept of neuropathic pain a 'multi-aetiological' entity and had direct implications for the labeling of recommendations. Indeed, most scientific societies now propose evidence-based recommendations for neuropathic pain in general.²,⁷⁷,⁹³⁻⁹⁵ Interestingly, the European Medicines Agency (EMA) has endorsed the concept of neuropathic pain as an entity and granted official approvals for use in neuropathic pain (for pregabalin and gabapentin, in particular), whilst the US Food and Drug Administration still gives official approvals in restricted neuropathic indications (diabetic painful neuropathies, postherpetic neuralgia, or spinal cord injury pain).

Based on the most recent evidence-based international recommendations supported by NeuPSIG, tricyclic antidepressants (amitriptyline and nortriptyline), SNRI antidepressants (particularly duloxetine), and gabapentinoids (gabapentin and pregabalin) are recommended as first line for peripheral or central neuropathic pain, whilst tramadol and topical agents (capsaicin high-concentration patches and lidocaine 5% plasters) are recommended as second line (for peripheral neuropathic pain as regards topical agents) and strong opioids as last choice⁷⁷ (Table 2). French revised recommendations based on a newer systematic study slightly amended this algorithm²: in particular, pregabalin was downgraded as second line because of modest results from recent double-blind trials¹⁰¹ and reporting of abuse and misuse (which tend to be higher than gabapentin), leading to a restricted usage in several countries, including France and UK.⁷⁹

Drugs, such as i.v. lidocaine or N-methyl-D-aspartate (NMDA) antagonist ketamine,¹⁰² or intrathecal ziconotide, a neuronal calcium channel blocker, are mainly recommended for refractory patients in restricted indications.² In contrast, a large number of drug therapies, including cannabinoids and anti-epileptics, are generally not recommended because of inefficacy or discrepant results in large-scale trials, although some anti-epileptics (oxcarbazepine, lamotrigine, and lacosamide) may be effective in patient subgroups.²,⁷⁷

## Newer avenues for the treatment of neuropathic pain

Recent meta-analyses of pharmacotherapy have indicated that only 30–40% of patients with neuropathic pain have an adequate response compared with placebo, and drug efficacy has become even poorer in recent meta-analyses.⁹²,¹⁰¹
<table><caption>**Table 2** Pharmacotherapy and main neurostimulation techniques with evidence from efficacy from RCTs and recommended for use in neuropathic pain by several scientific societies. Adapted and modified from Moisset and colleagues⁴ and Finnerup and colleagues.⁷⁷ EMA, European Medicines Agency; FDA, Food and Drug Administration; MME, morphine milligram equivalent; NP, neuropathic pain; rTMS, repetitive transcranial magnetic stimulation; SCS, spinal cord stimulation; SNRI, serotonin and noradrenaline reuptake inhibition; TENS, transcutaneous electrical nerve stimulation; TRPV, transient receptor potential vanilloid. *Transcranial direct current stimulation is not mentioned in this table because of less consistent efficacy than rTMS based on randomised controlled studies and lack of clear recommendation for use by scientific societies to date.</caption><thead><tr><td>Drugs and drug classes<sup>2,77</sup></td><td>Mechanism</td><td>Adverse effects</td><td>Precautions and contraindications</td><td>Modalities of use, level of recommendation, and official indications in Europe and in USA</td></tr></thead><tbody><tr><td>Amitriptyline, clomipramine, imipramine, nortriptyline, and desipramine</td><td>Monoamine reuptake inhibition, sodium channel block, and anticholinergic effects</td><td>Somnolence, anticholinergic effects, and weight gain</td><td>Cardiac disease, glaucoma, prostatic adenoma, seizure; high doses to be avoided in adults older than 65 yr of age</td><td>Doses 10–150 mg day<sup>-1</sup>; individual titration; recommended as first line except for older patients; EMA approval for neuropathic pain (no FDA approval for pain)</td></tr><tr><td>Duloxetine and venlafaxine</td><td>SNRI</td><td>Nausea, abdominal pain and constipation, and hypertension at high dosages for venlafaxine</td><td>Hepatic disorder (duloxetine), hypertension, cardiac disease, and use of tramadol</td><td>Duloxetine: 60–120 mg day<sup>-1</sup> in one or two divided doses; venlafaxine 150–225 mg day<sup>-1</sup>; recommended generally as first line; EMA/ FDA approval for diabetic painful neuropathy</td></tr><tr><td>Gabapentin, gabapentin extended release/enacarbil, and pregabalin</td><td>Act on alpha2delta subunit of voltage-gated calcium channels, which decreases central sensitisation</td><td>Sedation, dizziness, peripheral oedema, and weight gain</td><td>Reduce dose in renal insufficiency; potential for drug diversion and abuse</td><td>Gabapentin 1200–3600 mg day<sup>-1</sup> in three divided doses; pregabalin 150–600 mg day<sup>-1</sup> in two or three divided doses; recommended generally as first line (second line for pregabalin in recent French guidelines); EMA approval for peripheral neuropathic pain (gabapentin) or neuropathic pain (pregabalin); FDA approval for diabetic painful neuropathy, postherpetic neuralgia, and spinal cord injury pain (pregabalin)</td></tr><tr><td>Lidocaine 5% plasters</td><td>Sodium channel block</td><td>Local erythema, itching, and rash</td><td>Avoid in patients with skin irritation and known allergy to lidocaine</td><td>One to three plasters applied to the painful area for 12 h a day; recommended generally as second line for peripheral neuropathic pain (first line for frail and older patients); EMA/ FDA approval for postherpetic neuralgia</td></tr><tr><td>Capsaicin high-concentration patches (8%)</td><td>Transient receptor potential vanilloid Type 1 agonist</td><td>Pain, erythema, and itching; rare cases of high blood pressure (initial increase in pain)</td><td>No impairment of sensory evaluation after repeated applications; avoid in patients with skin irritation and precautions if used on the face</td><td>One to four patches applied to the painful area every 2–3 months for 30 min (feet) or 60 min (other body areas); recommended generally as second line for peripheral neuropathic pain; EMA/FDA approval for peripheral neuropathic pain</td></tr><tr><td>Tramadol</td><td>Mu receptor agonist; monoamine reuptake inhibition</td><td>Nausea, vomiting, constipation, dizziness, and somnolence</td><td>History of substance abuse, suicide risk, and risk of misuse on long-term use; avoid in combination with antidepressants (risk of serotonin syndrome); unpredicted pharmacokinetics (CYP450 genotype)</td><td>100–400 mg day<sup>-1</sup> in two divided dosages (sustained release); recommended generally as second line; no specific approval for neuropathic pain</td></tr><tr><td>Strong opioids (e.g. morphine, oxycodone, and methadone)</td><td>Mu receptor agonist; oxycodone may also cause kappa receptor antagonism</td><td>Nausea, vomiting, constipation, dizziness, and somnolence</td><td>History of substance abuse, suicide risk, and risk of misuse on long-term use</td><td>Individual titration; for doses ≥120 mg day<sup>-1</sup> of MME, refer to specialised centres; recommended generally as third line; no specific approval for neuropathic pain</td></tr></tbody></table>

Continued
<table><caption>Table 2 Continued</caption><thead><tr><td>Drugs and drug classes<sup>2,77</sup></td><td>Mechanism</td><td>Adverse effects</td><td>Precautions and contraindications</td><td>Modalities of use, level of recommendation, and official indications in Europe and in USA</td></tr></thead><tbody><tr><td>Botulinum toxin type A</td><td>Acetylcholine release inhibitor; potential central effects in neuropathic pain</td><td>Pain at injection site; potential risk of muscle hypotonia</td><td>Known hypersensitivity and infection of the painful area</td><td>100–400 units (5 units [2 cm]<sup>-2</sup>) in multiple i.d. or s.c. injections every 3 months; recommended generally as third line (specialised centres; off label) for peripheral NP</td></tr><tr><td>Neuro-stimulation<br>Transcutaneous electrical nerve stimulation<sup>2,121</sup></td><td>Initial hypothesis based on the gate control theory of pain; effects on descending endogenous opioid systems or GABAergic inhibition at the spinal cord level</td><td>Local pain and skin irritation</td><td>Avoid in patients with pacemaker and ongoing epilepsy</td><td>One to several sessions per day of 15–60 min duration with electrodes placed around the site of pain; self-administration at home; frequency and intensities to be set individually (generally high frequencies up to 100 Hz and high intensities seem to be more beneficial)</td></tr><tr><td>rTMS of the motor cortex<sup>*2,96<br>-98</sup></td><td>Effects on intracortical inhibition and facilitation; possible long-term effects on neuronal plasticity</td><td>Headache, migraine, and local pain at stimulation site</td><td>Contraindication in patients with cochlear implants, ongoing seizures, and past neurosurgical intervention; relative contraindications in patients with pacemaker</td><td>High-frequency (10 Hz or more) and high-intensity (≥1000 pulses per session) rTMS of the motor cortex; usual protocol is three to five daily sessions of rTMS followed by weekly then monthly sessions, but monthly sessions from the beginning may also be effective</td></tr><tr><td>Spinal cord stimulation<sup>2,99,100</sup></td><td>Initial hypothesis based on the gate control theory of pain; effects on descending endogenous opioid systems or GABAergic inhibition at the spinal cord level</td><td>Adverse events are rare (<15% of cases) and mostly include lead migration or breakage and infection</td><td>Ongoing psychosis and serious unstable disease; patients with total loss of sensation (absent somatosensory evoked potentials) expected to be non-responders)</td><td>Conventional SCS uses high-intensity stimulations (20–120 Hz) and induces paraesthesia in the painful area; SCS may be implanted percutaneously or surgically for patients with past spinal surgery (this allows to stimulate a larger area with surgical electrodes)</td></tr></tbody></table>
Furthermore, the development of drugs acting on new targets for neuropathic pain is challenging,<sup>103-106</sup> although a few newer drug classes might be promising.<sup>107</sup> Therefore, innovating strategies have become necessary to optimise neuropathic pain management. They include rational combination therapy, drug repositioning, neurostimulation techniques, and individualised pain management.

## Combination therapy

Combination therapy is frequently used by patients with neuropathic pain. Several high-quality studies have assessed the efficacy and safety of opioids combined with antidepressants or gabapentinoids and of gabapentinoids combined with antidepressants in neuropathic pain.<sup>108</sup> Although most studies did not find superiority of the combinations over monotherapies, one large-scale study found that the combination of duloxetine and pregabalin at moderate dosages (respectively, 60 and 300 mg day<sup>-1</sup>) was equivalent to monotherapy at high dosages (120 and 600 mg day<sup>-1</sup>, respectively) in patients who did not respond to monotherapy at moderate dosages.<sup>109</sup> The Optimal Pathway for Treating Neuropathic Pain in Diabetes Mellitus crossover study, including 130 people with painful diabetic neuropathy and suboptimal pain relief with monotherapy, compared the efficacy and safety of three treatment pathways, each lasting 16 weeks: amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin.<sup>110</sup> The mean pain intensity reduction on combination therapy was higher than for those who remained on monotherapy, and all pathways led to improved pain relief and similar safety. Combination therapy with antidepressants and gabapentinoids may therefore be considered when monotherapy with each of these drugs is insufficient.

## Drug repurposing

Antidepressants and anti-epileptics, primarily developed for depression and epilepsy, respectively, are typical long-established examples of drug repurposing for neuropathic pain.<sup>77</sup> Other classical examples of drug repositioning for neuropathic pain are represented by NMDA antagonists. These drugs block NMDA receptors, which play a major role in central sensitisation, an important mechanism of neuropathic pain. They include ketamine<sup>102</sup> (an i.v. anaesthetic) and oral NMDA antagonists, such as dextromethorphan (a widely used antitussive agent), amantadine (used for Parkinson's disease), and memantine (approved for the treatment of Alzheimer's disease).<sup>111</sup> However, the efficacy of oral NMDA antagonists is less established in neuropathic pain.<sup>111</sup>

More recent examples of successful drug repositioning include botulinum toxin A (BTX-A) and mexiletine. BTX-A, a potent neurotoxin used for focal muscle hyperactivity (dystonia and focal spasticity) is a good example of successful drug repositioning. The beneficial effect of BTX-A in muscle disorders results from the blockade of presynaptic nerve terminals releasing acetylcholine.<sup>112</sup> However, early in the use of BTX-A for dystonia, the authors had noticed that pain relief preceded the cessation of muscle contraction and exceeded what would be expected solely as a consequence of muscle relaxation. These findings suggested that BTX-A might have analgesic properties independently of its myorelaxant action. The sustained effects for up to 3 months of one or two repeated administrations of BTX-A (100–300 U) injected intradermally or

subcutaneously into the painful area were further reported in neuropathic pain by several independent teams.<sup>113,114</sup> It is hypothesised that the efficacy of BTX-A is related to central mechanisms through retrograde axonal transport.<sup>115</sup> BTX-A is now recommended generally as third line for peripheral neuropathic pain, but it has no approval for use in this indication<sup>77</sup> (Table 2). Despite safety concerns, oral mexiletine, an old anti-arrhythmic drug with sodium channel-blocking properties, has recently been repositioned for primary erythromelalgia (a genetic condition characterised by burning pain and vasomotor changes aggravated by heat), the mechanisms of which involve a gain of function mutation on Nav1.7 sodium channels.<sup>116,117</sup>

Lastly, a potentially relevant example of drug repositioning for neuropathic pain includes ambroxol, used for decades for its antitussive or anti-secretory properties. Indeed, this drug has potent sodium channel-blocking properties by targeting Nav1.7 and Nav1.8 channels and anti-inflammatory benefits and holds promise as a topical formulation.<sup>118</sup>

## Neurostimulation

Because of the limitations of pharmacotherapy, other approaches based notably on neurostimulation have been sought for neuropathic pain.<sup>96,99,100</sup> Conventional neurostimulation approaches include transcutaneous electrical nerve stimulation (TENS) (a noninvasive technique, which uses adhesive electrodes applied to the skin surface to apply pulsed electrical stimulation inducing paraesthesia) and spinal cord stimulation (SCS) (an invasive technique, which consists in connecting an electrode inserted epidurally to a stimulator implanted in the abdominal wall or buttock), whilst emerging techniques include noninvasive brain neurostimulation.

Contrasting with the empirical development of drug therapy for neuropathic pain, the use of TENS and SCS has been directly linked to rationale scientific hypotheses, with the publication in 1965 in *Science* of the classical 'gate control theory' by Melzack and Wall.<sup>119</sup> This theory emphasised for the first time the role of central modulation in the experience of pain by showing that afferent input from large fibres may inhibit pain transmission conveyed by nociceptive afferents at the dorsal horn level. As early as 2 yr later, it was followed by clinical applications, with the development of implantable SCS by Shealy and colleagues,<sup>120</sup> then the broad dissemination of TENS.<sup>121</sup> Both techniques were initially supposed to act by inhibiting pain transmission through effects on large afferents (which induces paraesthesia in the painful area), but it is now largely established that they are also able to act on supraspinal descending inhibitory controls.<sup>122</sup> The level of evidence for efficacy of TENS is considered as very low in neuropathic pain despite a few placebo-controlled trials,<sup>121</sup> but it may be recommended because of its excellent safety.<sup>2</sup> SCS has been assessed in diabetic painful neuropathy, failed back surgery syndrome, and complex regional pain syndrome,<sup>2,99,100</sup> but the validity of RCTs has been challenged because of blinding issues (attributable to paraesthesia) and debatable choice of control groups (generally standard of care).<sup>123,124</sup> Newer stimulation paradigms, which do not induce paraesthesia, have emerged, including stimulation of the dorsal root ganglion or high-frequency, burst, or closed-loop SCS.<sup>99,125,126</sup> Whilst positive results from large-scale multicentre open-label studies have been reported,<sup>99,125,126</sup> the only placebo-controlled study to date has reported negative results with
high-frequency SCS in painful radiculopathy.¹²⁷ However, the primary endpoint of this trial was not pain but disability. Conventional SCS might also have broader mechanisms of action and higher efficacy than newer SCS techniques.

Regarding brain neuromodulation, invasive techniques have long preceded noninvasive stimulation. Deep brain stimulation of the thalamus was introduced by Hosobuchi and colleagues¹²⁸ in 1973 then Mazars¹²⁹ in 1975, a few years after the discovery in the cat of descending inhibitory controls by Reynolds in 1969.⁹⁹ In 1991, Tsubokawa and colleagues¹³⁰ reported in the same publication the effect of epidural motor cortex stimulation in animals and in seven patients with central pain, outlining the remarkably rapid translational implication of their experimental results. Following these pioneering works, a number of prospective (generally open label) studies have reported the efficacy of epidural motor cortex stimulation in chronic refractory neuropathic pain.⁹⁶ Two small, crossover, single-centre double-blind studies have also been conducted¹³¹,¹³² with positive results in 40% of the patients in the more recent study¹³¹ but negative results against placebo in the first one.¹³² These invasive techniques are now restricted to a few neurosurgical centres for refractory patients.

Noninvasive brain stimulation includes mainly repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). rTMS uses a transient magnetic field to produce electrical currents in the cortex.¹³³ Neuropathic pain is only relieved by the use of high-frequency (5–20 Hz) stimulation of the contralateral primary motor cortex and using high intensities of stimulation (generally between 1500 and 2000 pulses per session).⁹⁶,¹³⁴ Most initial studies used single sessions, which produced delayed (2–4 days) and short-lasting analgesic effects for a few days. These studies mainly aimed at predicting the effects of epidural motor cortex stimulation.⁹⁶,¹³⁴ They were limited by lack of true double blinding, because they used two coils (one active and one sham), and the investigator in charge of placing the coil was not blind for the treatment.¹³⁵ Two recent placebo-controlled studies using robotised neuronavigation and a true double-blind design with a biface coil (one sham and one active) confirmed the efficacy of repeated sessions of rTMS of the primary motor cortex (M1) in patients with peripheral neuropathic pain (in a multicentre trial over 24 weeks)⁹⁷ and in central neuropathic pain (in a single-centre crossover trial over 16 weeks).⁹⁸ Safety was excellent, the main side-effects being transient headache. In contrast, results regarding the efficacy of targeting other cortical targets (prefrontal cortex and insular cortex) have been disappointing.⁹⁷,¹³⁶ Therapeutic perspectives include newer cooled coil (Hesed coil), which allows deep brain stimulation over a larger cortical surface.¹³⁷,¹³⁸ Another neurostimulation technique is tDCS, which modulates neuronal excitability by applying weak electric current to the skin.⁹⁶,¹⁰⁰ Although its efficacy seems lower than that of rTMS in peripheral neuropathic pain¹³⁹ and results have been heterogeneous against placebo,¹⁰⁰ the use of home-delivery tDCS systems is expanding.⁹⁶,¹⁴⁰

## Towards individualised therapeutic approach for neuropathic pain

There is a large expert consensus that an individualised therapeutic approach has the best chance to increase success

in neuropathic pain.⁶⁴,¹⁴¹,¹⁴² Stratification of patients may be based on various biomarkers (genetics, electrophysiology, skin punch biopsy, and imaging).¹⁴³ In particular, recent studies using genotype identification have shown that patients with painful small fibre neuropathies and specific voltage-gated sodium channel variants were good responders to drugs primarily blocking sodium channels, such as lacosamide.¹⁴⁴ However, the easiest way to achieve this strategy in large-scale clinical trials is to stratify patients as per their sensory phenotype.⁶⁴,¹⁴¹,¹⁴²,¹⁴⁵ The underlying concept for this approach comes from clinical studies showing that within well-defined neuropathic pain conditions (e.g. diabetic painful neuropathies or postherpetic neuralgia), distinct patterns or distinct clusters of symptoms or signs may be identified, which may be linked to specific mechanisms.¹⁴⁵⁻¹⁴⁷ Only two RCTs in peripheral neuropathic pain used a predefined stratification of patients based on quantitative sensory testing and yielded discrepant results,⁶⁸,¹⁴⁸ whilst exploratory analyses of multiple trials based on quantitative sensory testing¹⁴⁹⁻¹⁵² or specific neuropathic pain questionnaires, such as the NPSI,⁶⁹,⁷⁰,¹⁵³ have suggested the relevance of this approach (Table 1). Stratifying patients with neuropathic pain in clinical trials based on their sensory phenotype is now advocated by EMA (https://www.ema.europa.eu/en/clinical-development-medicinal-products-intended-treatment-pain-scientific-guideline) but remains marginal as a predefined approach in large-scale trials.¹⁵⁴

## Conclusions and recommendations

Over the past decades, a considerable number of clinical research studies have been devoted to neuropathic pain. These studies have contributed to standardise the definition and classification of neuropathic pains, develop questionnaires to detect neuropathic pain or quantify its symptoms, recognise acute neuropathic pain and predict chronic neuropathic pain particularly after surgery, and implement multicentre trials of pharmacotherapy and neurostimulation techniques. Newer clinical trials should take into account the diversity of patients with neuropathic pain and stratify them based on their sensory phenotype or other biomarkers. They should also further assess the place of combination therapy and of neuromodulation techniques to optimise therapeutic response. The development of drugs acting on new mechanisms, although subject to many obstacles to date, remains essential, whilst the repositioning of old drugs for neuropathic pain may also contribute to optimise therapeutic management.

## Authors’ contributions

NA prepared the first version of the manuscript, LC drafted the paragraphs on acute pain and COVID-19 and DB and LC checked, amended and modified the manuscript.

## Declarations of interest

NA is an editor of the *British Journal of Anaesthesia* and has received honoraria from Merz, Grünenthal, Pfizer, Biogen, Upsa, Air Liquide and Novartis over the past 36 months. LC is a member of the editorial board of editors of the *British Journal of Anaesthesia* and has received honoraria from CHANGEpain and Anderson Cancer Center (Houston, TX, USA) for educational webinars. DB has received honoraria from Air Liquide,
Grünenthal, and Bayer over the past 36 months and is a member of the IMI-Pain Care consortium.

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Handling editor: Jonathan Hardman