The 2nd International Conference on 

Controversies in Neuropathic Pain

Chronic neuropathic pain is often difficult to treat and research into risk factors and prevention is important. In recent years, there have been a focus on mechanisms and risk factors for the “transition of acute to chronic pain”. Acute pain is most often a transient nociceptive pain and it has been proposed that there may be a shift from a “physiological” to a “pathological” pain, when pain become chronic. However, in neuropathic pain, the pain may be “pathological” from the beginning. There is limited research into acute neuropathic pain. Neuropathic pain may occur immediately after a disease or lesion of the somatosensory nervous system but the onset may be delayed. Prospective studies in neuropathic pain due to stroke, spinal cord injury, and surgery suggest that early sensory hypersensitivity and paresthesia or dysesthesia can precede the onset of an ongoing chronic neuropathic pain. We need better tools to identify neuropathic pain early in order to understand the mechanisms underlying the onset and resolution or persistence of acute neuropathic pain.

Pharmacotherapy, including non-opioid and opioid analgesics, is an important cornerstone in the multimodal management of chronic pain. Opioids are recommended for the treatment of moderate to severe cancer pain in all recent guidelines. However, the use of opioids in the management of non-cancer-related pain, including neuropathic pain, is the topic of much debate and many national and international bodies have published updated guidelines and recommendations.

Recently, the European Pain Federation EFIC formulated clinical practice recommendations.

The key clinical practice recommendations suggest: (a) first optimizing established non-pharmacological treatments and non-opioid analgesics and (b) considering opioid treatment if established non-pharmacological treatments or non-opioid analgeics are not effective and/or not tolerated and/or contraindicated. It should be stressed that the value of opioid therapy must be confirmed for each patient through differential diagnosis, and by weighing up the risk of comorbidities and the potential for opioid‐related adverse effects and substance abuse. Based on at least one RCT, opioids achieve improvements of pain and function compared to placebo at the cost of a lower tolerability in some neuropathic pain syndromes such as painful non-diabetic polyneuropathy, phantom limb pain, radicular pain and central neuropathic pain after spinal cord injury. For all other neuropathic pain syndromes, the clinical practice statement states that it can be considered based on expert consensus. Importantly, opioid treatment should be tapered and stopped if the individual therapeutic goals are no longer achieved, or insufficiently treatable or intolerable adverse events occur, or the individual therapeutic goals are achieved by other medical, physiotherapeutic, physical or psychotherapeutic measures, and finally if people prescribed with opioids diverse and /or use the prescribed opi­oid in an abusive manner despite complementary treatment from a dependence specialist.

In conclusion, opioids can be a ‘go’ in well selected patients with non-cancer neuropathic pain as part of a comprehensive, multimodal, multidisciplinary approach to treatment.

Key reference

Häuser W, Morlion B, Vowles KE et al. Eur J Pain. 2021 May;25(5):949-968.

Complex Regional Pain Syndrome (CRPS) starts with an inciting event. Within some few days after a limb trauma, patients develop a characteristic combination of visible inflammatory signs and pain which is not related to the initial trauma anymore. It is intriguing that women in their middle ages are mainly at risk for CRPS. Not only pain but also autoimmune disorders are highly prevalent in this population. Histologic investigations have shown that in the acute phase of CRPS when inflammatory signs are prevalent, mast cells and keratinocytes proliferate in the affected skin, they become activated and produce a plenty of inflammatory cytokines as surrogates of innate immune system activation. In parallel, IgM autoantibodies, directed against different intracellular proteins (e.g. keratin, actin, enolase, histone), emerge and sensitize for pain in the skin (IgM from acute CRPS) and particularly the spinal cord (IgM from acute and chronic CRPS). This sensitization requires complement C5a activation and probably induces the release of hyperalgesic substances like cytokines. In case of chronic CRPS when pain prevails although there is a reduction of the local inflammatory signs, autoantibodies of IgG classes activate dorsal horn glia cells which again release hyperalgesic cytokines. Other investigations proved autoantibodies directed against autonomic receptors and endothelial cells in CRPS. This whole series of experiments proves that the adaptive immune system significantly contributes to pain and suffering in CRPS. Although it is unlikely that one mechanism explains CRPS comprehensively, the knowledge about autoimmunity after a trauma opens new possibilities for a targeted pain treatment in CRPS.

Neuropathic pain in children can be severe and persistent. Recognition based on clinical history and sensory descriptors is feasible in older children and adolescents; modified neuropathy scales have identified chemotherapy-induced symptoms and signs; and neuropathic screening tool scores are increasingly reported and require ongoing validation.¹ Common causes differ from adults, and diseases that are rare but present in childhood² and have specific management implications need to be considered. Using quantitative sensory testing, we have identified distinct sensory profiles in adolescents (10-18 years) with peripheral neuropathic pain³ that parallel those reported in adults (ie. thermal hyperalgesia, mechanical hyperalgesia, sensory loss). Pharmacotherapy is largely extrapolated from adult data as evidence from paediatric populations is limited, and the significant impact of neuropathic pain on physical and emotional function and quality of life highlight the need for multidisciplinary management.

1. Walker SM. Neuropathic pain in children: Steps towards improved recognition and management. EBioMedicine 2020;62:103124.
2. Arthur L, Keen K, Verriotis M, Peters J, Kelly A, Howard RF, Dib-Hajj SD, Waxman SG, Walker SM. Pediatric Erythromelalgia and SCN9A Mutations: Systematic Review and Single-Center Case Series. J Pediatr 2019;206:217-24 e9.
3. Verriotis M, Peters J, Sorger C, Walker SM. Phenotyping peripheral neuropathic pain in male and female adolescents: pain descriptors, somatosensory profiles, conditioned pain modulation, and child-parent reported disability. Pain 2021;162(6):1732-48.

Pharmacological inhibition of neurotransmitter release and/or ectopic impulses by afferent nociceptor terminals in the periphery or dorsal spinal cord have long been regarded as key mechanisms mediating the effects of some treatments for chronic neuropathic pain.  However, there is increasing evidence that pathophysiological mechanisms at the DRG itself may underlie neuropathic pain, particularly in clinical neuro-inflammatory and immune conditions, thus providing a target for current and novel analgesic treatments.

Data will be presented which show that in clinical painful neuro-inflammatory and immune conditions, such as Sjogren’s syndrome and voltage-gated potassium channel antibody disease, which are non-length dependent, the pathophysiological mechanism lies within the DRG and adjacent nerve roots; skin punch biopsies in such patients show increased regenerating nerve fibres marked by GAP-43, a pattern different from the length-dependent “dying-back” painful neuropathies, such as painful diabetic neuropathy.

Marshall Devor has shown the potential role of ectopic electrogenesis in DRGs in models: subthreshold oscillations, enhanced in neuropathies, are sensitive to Na+ channel blockers and other membrane stabilizing drugs at lower concentrations than required to block impulse propagation along sensory axons.  He has proposed that systemically or locally administered drugs that suppress neuropathic ectopia at DRG within a therapeutic window may advance treatment, providing greater efficacy but reduced side-effects.  The efficacy and advantages of DRG neuromodulation has been shown by many groups.

In summary, this talk will highlight DRG pharmacological pain targets, including satellite cells expressing NGF and other neurotrophic factors, and abnormal nerve sprouting.  The role and efficacy of local and systemic immune therapies such as IVIg will be discussed, with regard to both the effect on chronic neuropathic pain and disease-modification.

Quantitative Sensory Testing can assess multiple aspects of the sensory nervous system, including peripheral and central aspects, sensation and pain thresholds, and integrity of various pathways. Using comprehensive protocols in a standardized way, QST can thus paint a picture of the individual sensory alterations of each patient. Some of the emerging patterns have been linked to well-characterized surrogate models, indicating a link between patterns seen in patients and mechanistic studies. Although only few studies have been prospectively designed to test differential treatment response, the existing evidence points towards that specific treatments will be more efficient for patient groups with certain sensory patterns. It has also been shown that QST profiles change in response to worsening of the condition or improvement due to disease-modifying treatment. Thus, QST has demonstrated all elements of a biomarker: differentially responsive to treatment, linked to plausible mechanisms of disease, and responsive to changes in disease.

Evoked pain responses are excellent tests to assess small fiber function and are highly valuable to diagnose small fiber neuropathy. Thus, in chronic pain patients QST is an important tool for the diagnosis of neuropathy. However, only a minority of patients with peripheral neuropathy develop chronic pain and therefore it is crucial to understand the mechanisms that differentiate between painful and painless neuropathy. Unfortunately, QST profiling does not contribute to this differentiation. Moreover, neuropathic pain patients with hyperexcitable nociceptors (NaV1.7 mutations) do not show a hyperexcitable nociceptor QST profile, whereas such a hyperexcitable nociceptor profile is found in the same percentage of about 10% in patients with strong neuropathic pain and painless neuropathy. These examples through serious doubts on the idea that QST profiles are linked to certain pain mechanisms. Recent data on painful carpal tunnel syndrome even found that QST thresholds in the neighboring non-affected skin are reversibly impaired by the ongoing pain; such impact of ongoing pain on QST results would even reverse the suggested mechanistic chain. Obviously, QST results do not correlate to the clinically most relevant ongoing pain and suprathreshold pain responses. In animal research, enormous efforts are being undertaken to generate parameters allowing quantification of ongoing pain and suprathreshold pain responses. We should avoid transferring the limitations from animal behavior to clinical research. Rather, we crucially need to develop and validate tests for phenotyping patients that correlate to clinically relevant aspects of their pain and suffering.

Neuropathic pain affects 7–10% of the population and is often ineffectively and incompletely treated. Although the gold standard for treatment of neuropathic pain includes tricyclic antidepressants (TCAs), serotonin-noradrenaline reuptake inhibitors, and anticonvulsants, patients suffering from neuropathic pain are increasingly turning to nonpharmacologic treatments, including nutritional supplements for analgesia. So-called “nutraceuticals” have garnered significant interest among patients seeking to self-treat their neuropathic pain conditions including disorders such as  diabetic neuropathy, chemotherapy related neuropathic pain, and fibromyalgia amongst many others with readily available supplements. The supplements most often used by patients include vitamins such as vitamin B and vitamin D, trace minerals zinc and magnesium, and herbal remedies such as curcumin and St. John’s Wort. However, evidence surrounding the efficacy and mechanisms of these supplements in neuropathic pain is limited, and the scientific literature consists primarily of preclinical animal models, case studies, and small randomized controlled trials (RCTs).  We will discuss the evidence behind the use of these agents as well as discuss needs for large randomized controlled trials to more fully inform patients and physicians on the utility of these supplements in neuropathic pain.