Chronic pain is defined as any type of pain that persists more than three months following the initial triggering event (Scholz et al., 2019). Around 20% of the population worldwide is affected by this condition, and multiple disorders are associated with chronic pain, including mood disorders such as anxiety and major depressive disorders that affect 50% of patients with chronic pain. Chronic pain and its comorbidities are thus one of the most important causes of disability and impaired quality of life, with a societal cost that can reach $700 billion in the United States, and over €340 billion in the European Union annually (Barham, 2012; Institute of Medicine (U.S.), 2011). Among its seven diagnostic categories defined by the 11th revised International Classification of Diseases and related health problems (ICD-11), neuropathic pain is one of the most prevalent pain conditions, affecting one in ten adults worldwide (Scholz et al., 2019).

Neuropathic pain is defined as a pain caused by a lesion or disease affecting the somatosensory system (Jensen et al., 2011; Treede et al., 2008). It can originate peripherally (nerves, plexus, etc.) or centrally (spinal cord and brain). Neuropathic pain can result from trauma (spinal cord injury, carpal tunnel syndrome, etc.), metabolic disorders (peripheral diabetic polyneuropathy), viral infections (postherpetic neuralgia, Human Immunodeficiency Viruses-1 (HIV)), autoimmune disorders (multiple sclerosis) and chemotherapeutics affecting the nervous system (for review see (Baron et al., 2010)). Due to its diverse etiology, neuropathic pain remains difficult to diagnose clinically, especially when comorbid with other pathological conditions. As there is no generalizable classification allowing a clear diagnosis, a grading system, proposed by International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG), is often used (Finnerup et al., 2016). However, this grading system only determines the level of certainty for the presence of a neuropathic pain (possible, probable or definite) based on the patient's history, tests confirming lesions or diseases affecting the nervous system, and the neuroanatomical distribution of pain and its association with sensory signs. Symptoms of neuropathic pain include the presence of (i) paroxysmal or spontaneous pain, (ii) evoked pain, (iii) abnormal sensations, and/or (iv) sensory deficits (Bennett et al., 2007; Rasmussen et al., 2004). Paroxysmal pain corresponds to episodic pain that can occur several times a day and is described as a sensation of electrical shocks or stabbing, while spontaneous pain is a constant dull pain that can be described as sensation of cold, burning or itching associated with pins and needles. On the other hand, symptoms of evoked pain include allodynia (pain due to a stimulus that does not normally provoke pain), hyperalgesia (increased pain from a stimulus that normally provokes pain), and hyperpathia (abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold). Abnormal sensations include paresthesia and dysesthesia, corresponding to stinging or tingling sensations that can be spontaneous or evoked. Finally, sensory deficits include partial or total loss of sensation of cold, warm or touch (hypoesthesia) in the painful area.

Treatment of neuropathic pain is challenging due to its heterogenic etiologies, lack of objective diagnosis tools and its resistance to classical analgesic drugs. As a result, neuropathic pain management strategies focus primarily on treating symptoms. According to NeuPSIG, subclasses of classical antidepressant drugs and anticonvulsants remain among the first-line treatments for many neuropathic pain conditions (Attal et al., 2010). Lidocaine, capsaicin, tramadol and tapentadol are recommended as second-line treatment while third-line treatments for neuropathic pain include strong opioids and Botulinum Toxin type A (BoNT/A) (Colloca et al., 2017; Dworkin et al., 2007) (Table 1). Besides these drugs, non-pharmacological alternatives such as neuromuscular and neuronal stimulations are used especially when none of the classical drugs is efficient, or as adjuvant therapy (Fig. 2). Finally, several clinical trials (Table 2) and preclinical studies (Table 3) have been conducted to develop therapeutic targets that are more specific, more potent and/or with less side effects.

In this review, we will first describe the mechanisms of action, limitations and side effects of the current pharmacological treatments recommended for neuropathic pain. We will then focus on promising recently developed clinical and preclinical targets and their mechanism of action (Fig. 1). Finally, we will discuss the existing alternative non-pharmacological approaches, with their known mechanisms (Fig. 2), efficacy and limitations, and their prospective application to potentiate pharmacological treatments.