Nociplastic Pain, Small Fiber Neuropathy & Chronic Low Back Pain

Nociplastic pain is “pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain” (Kosek et al 2016).

Central sensitization is a central process to this experience. Central sensitization encompasses impaired functioning of inhibitory, descending anti-nociceptive mechanisms (Meeus et al., 2008), and over activation of descending and ascending pain facilitatory pathways (Staud et al., 2007, Meeus and Nijs, 2007). The presentation includes a) increased activity in areas active during acute pain sensations such as the insula, anterior cingulate cortex and the prefrontal cortex (Seifert and Maihöfner, 2009), and increased activity in regions  not involved in acute pain sensations in healthy patients such as various brain stem nuclei, dorsolateral frontal cortex and parietal associated cortex (Seifert and Maihöfner, 2009). Once central sensitization is established, the nociceptive input from a new peripheral injury may sustain or aggravate the process of central sensitization (Affaitati et al 2011).

Schrepf et al (2018) state the hallmark symptoms of centralized pain include widespread pain, fatigue, negative affect, unrefreshing sleep, and cognitive dysfunction. This family of conditions characterized in part by pain and varied constitutional symptoms, such as fibromyalgia, temporomandibular disorder, and chronic pelvic pain, play a significant role in the societal burden of chronic pain, due to prevalence and difficulty to treat. These and other pain conditions are referred to as chronic overlapping pain conditions because they so often co-occur in both individuals and families (Veasley et al 2015). Functional, chemical, and structural neuroimaging studies reveal abnormalities in the brains of patients with chronic overlapping pain conditions (Schrepf et al 2018). This general pattern has been noted in people that may be considered healthy where the symptoms aren’t at an impactful level (Wolfe 2009). Perhaps showing an early non-symptomatic stage.

Schrepf et al (2018) coined the terms generalized sensory sensitivity and SPACE (Sleep, Pain, Affect, Cognition, Energy). Generalized sensory sensitivity may be best understood as a tendency to experience, notice, and report increased sensitivity to external stimuli across multiple sensory modalities, increased sensitivity to symptoms or sensations occurring within the body (somatic awareness), and pain or tenderness (hyperalgesia/allodynia) in multiple regions of the body. In their study of 1039 patients the generalized sensory sensitivity symptoms were more were frequently noted in chronic overlapping pain conditions than the SPACE symptoms (Schrepf et al 2018).

Changes to the central nervous system provide the simplest explanation for the co-occurrence of symptoms such as sensitivity to many different sensory experiences, widespread pain, and the memory, sleep, and mood issues observed in most chronic overlapping pain conditions (Clauw 2014). Indeed work in rheumatoid arthritis has demonstrated that higher levels of fibromyaglia symptoms are associated with the same functional connectivity findings seen in centralized pain conditions such as fibromyalgia (Napadow et al. 2010) specifically, an increase in positive connections between the default mode network and insular cortex as “fibromyalgianess” increases (Basu et al. 2014). The same pattern is evident in chronic low back pain (Loggia et al 2013).

Abnormal regulation and output of the hypothalamic-pituitary-adrenal (HPA) axis is commonly associated with nocipathic pain disorders (Eller-Smith et al 2018). The HPA axis is the primary stress response system and its activation results in downstream production of cortisol and a dampening of the immune response. Eller-Smith et al (2018) go further suggesting patients with “centralized” pain syndromes often present with hyper- or hypocortisolism and evidence of altered downstream signaling from the HPA axis. This includes increased Mast cell (MC) infiltration and activation, which can sensitize nearby nociceptors. Thus with chronic activation, it is possible chronicity could ensue.

Could Small Fiber Neuropathy Play A Part In Nociplastic Pain?

A small fiber neuropathy occurs when damage to the peripheral nerves predominantly or entirely affects the small myelinated (Aδ) fibers or unmyelinated C fibers (Hovaguiman and Gibbons 2011). These are small somatic and autonomic fibers involved in autonomic and enteric function as well as thermal perception and nociception. C-fibers convey nociception to the CNS, they also have an ‘efferent’ function, controlling vasodilatation of the skin arterioles, mediating axon-reflexes locally and/or centrally (dorsal root reflexes) by release of neuropeptides from the terminals of the nociceptive afferents (Herman et al 2007).

The incidence of small fiber neuropathy in non-specific chronic low back pain has not been investigated but was as high as 64% in one study of chronic pelvic pain patients (Chen et al 2018). The incidence of other members of the chronic overlapping pain syndromes were; low back pain was 33%, fibromyalgia 38%, migraines 38%, irritable bowel syndrome 33% and reflux 46%. It is clearly possible that damage to the small nerve fibers could contribute to these syndromes both as an independent cause and in concert with other causes. 

10.1177_1179573518771703-fig1.jpg

Figure 1 Symptoms of Small Fiber Neuropathy (Levine 2018)

Symptoms can typically occur with a “stocking” distribution in the lower limbs and “glove” distribution in the upper limb. Symptoms can occur in a non-length dependant fashion affecting other areas.  Many symptoms worsen during periods of rest and at night. In addition to spontaneous pain, many individuals report allodynia and hyperesthesia. Patients with small fiber neuropathy frequently complain that the bedsheets are exquisitely painful. Autonomic and enteric symptoms include dry eyes, erectile dysfunction, nausea, vomiting, dry mouth, postural lightheadedness, presyncope, syncope, abnormal sweating, diarrhea, constipation, early satiety, voiding, difficulty with urinary frequency and nocturia. It is easy to see the carry over with the symptoms of nociplastic pain, SPACE and generalised sensitivity as described above.

Figure 2. Causes of Small Fiber Neuropathy

The common causes included diabetes, vitamin B12 deficiency, sarcoidosis, HIV, neurotoxic medications such as radiotherapy, thyroid dysfunction, celiac disease, paraneoplastic syndromes, and paraproteinemias (Hovaguiman and Gibbons 2011). 50% of patients with small fibre neuropathy end up with a diagnosis of idiopathic (Hsieh 2010). 

Half of idiopathic small fiber neuropathy patients have abnormal 2 hour glucose tolerance test or abnormal fasting glucose levels (Sumner et al 2003, Singleton et al 2001). Although other authors suggest 90% are idiopathic (Barohn  1998). Some authors have suggested peripheral neuropathies may begin before the onset of diagnosable diabetes (Holland and Prodan 2004).

In a study of 58 obese subjects signs of small fiber neuropathy were prevalent in a skin area without neurological symptoms or signs and in subjects with and without hyperglycemia and hyperinsulinemia (Herman et al 2007). 

In 38 patients with hypothyroidism and pain in the extremities 100% had signs of small fiber neuropathy with a mixture of increased and decreased thermal thresholds evident (Ørstavik et al 2006). 

Small nerve fiber neuropathy may occur secondary to celiac disease without any gastrointestinal symptoms (Brannagan et al 2005). Specifically CCR9 expression is reduced on epithelial and lamina propria T cells in untreated celiac disease. Down-regulation of CCR9 persists in intraepithelial T cells from well-treated patients (Olaussen et al 2007). Reduced chemokine receptor 9 on intraepithelial lymphocytes in celiac disease suggests persistent epithelial activation. The chemokine receptor 9 (CCR9) is a small intestinal homing receptor normally found on most mucosal T cells in this organ. This suggests ongoing immune activation preferentially within the epithelium secondary to exposure to gluten in sensitive indiviudals. Furthermore, gliadins, a component in gluten, have endotoxin-like effects (Laparra Llopis et al 2010), and can elicit proinflammatory cytokine production (Jyonouchi et al 2002). Increased proinflammatory cytokine levels have been implicated in small fiber neuropathy (Uceyler et al 2010).

To date I have been unable to find any authors discussing the potential for multifactorial causes. For example an underlying genetic predisposition such as hypermobility Ehlers-Danlos syndrome, gluten sensitivity, elevated fats and systemic inflammation through dietary causes. Such a pattern is physiologically feasible but needs investigation in animal models. 

Fibromylagia & Small Fiber Neuropathy

Fibromyalgia patients commonly use neuropathic terms to describe their pain, to a similar extent to those with known neuropathic conditions (Koroschetz et al 2011).

Caro et al (2008) showed via sural nerve biopsy that fibromyalgia patients had demyelination there without signs of amyloidosis or vasculitis.  Later, Caro and Winter (2014) found the calf and thigh epidermal nerve fiber density in patients with fibromyalgia was significantly diminished compared with that of control subjects. These changes were inversely correlated with serum levels of IL-2R, although not to a statistically significant level.

Diet, the Gut Microbiome, Nocipathic Pain, Small Fiber Neuropathy and Chronic Low Back Pain

Mice fed a western diet for 6 weeks, were ‘overweight’, developed gut microbiota dysbiosis, altered faecal metabolites, increased intraluminal lipopolyssacharide, increased plasma free fatty acid levels and later loss of motorneurons (Reichardt et al 2017). Unlike a high fat diet, a western diet did not elicit hyperglycaemia, endotoxaemia and inflammation. Suggesting the need to define key differences between the effect of high fat diet and western diet on gut microbiome and metabolic profiles. The western diet caused gastrointestinal dysmotility before the overt loss of nitrergic motorneurons, suggesting enteric nervous system function changes occur before injuries can be seen microscopically. It highlights the need to study the effects of a western diet on the ENS and neuromuscular physiology. A high fat diet in mice causes apoptotic loss of nitrergic myenteric neurons in the small and large intestine via an activated caspase‐3 signalling pathway (Reichardt et al 2017). Reichardt et al’s (2017) findings suggest that free fatty acids from a western diet trigger nitrergic myenteric neurons cell death in colon before ileum. Western diet induced damage to nitrergic myenteric neurons is not associated with the activation of caspase‐3. Thus the possibility for diet induced small fiber neuropathy exists. 

Is Hypermobile Ehlers-Danlos Syndrome A Risk Factor For Small Fiber Neuropathy?

Background On Hypermobile Ehlers-Danlos Syndrome

In a study of 12,853 participants 3.4% had joint hypermobility and widespread considered a proxy for Hypermobile Ehlers-Danlos syndromes (hEDS) (Mulvey et al 2013). hEDS previously EDS type III, is a heritable connective tissue disorder associated with generalised hypermobility, musculoskeletal symptoms and milder skin changes than the classical and vascular types. It is the only major type of EDS without a known molecular defect (Tinkle et al 2017). 

The concordance of joint hypermobility among dizygotic twins was 36% in 472 female twin pairs, whereas monozygotic twins had a concordance rate of 60% in 483 female twin pairs indicating a strong genetic trait with epigenetic and/ or environmental influences (Hakim et al, 2004). The ratio of females to males affected is between 9:1 to 2:1 (Castori et al 2010). The incidence of chronic pain is higher in females as well and common mediators such as hormonal fluctuations and psychological factors likely contribute. 

Tinkle et al (2017) state on behalf of an international consortium on Ehlers-Danlos Syndrome that Ehlers-Danlos Syndrome cannot clinically be distinguished from generalised hypermobility and the two coexist as part of a spectrum. 

Three distinct phases of progression have been identified in hEDS patients as, “hypermobile”, “pain” and “stiffness” (Castori et al 2010). These are correlated with a decrease in the Beighton score and tendency for the score to go negative, <5/9 in the patients 40s (Castori et al 2011). 

The hypermobility phase is associated with fatigue, lower limb pain, pain on fine motor control and forms of delayed development such as dyspraxia. The two more common patterns of presentation are, a limited number of painful and/or unstable joints or chronic widespread musculoskeletal pain. In the former group, the more common problematic or unstable joints often presenting with recurrent subluxations/dislocations or pain are the shoulder, knee, and ankle. The pain phase can start from the second to forth decades and is often diagnosed fibromyalgia (Ting et al 2012), and shares several features with chronic overlapping pain conditions. Treatment resistant gastrointestinal complaints, orthostatic intolerance, headaches, chronic fatigue, sleep disturbances, anxiety, depression, temporomandibular joint pain and generalised pain are common symptoms (Tinkle et al 2017). The stiffness phase is associated with an escalation of pain and reduced range of motion (Tinkle et al 2017). 

The skin is less loose than in other forms of EDS and failures of the pelvic and abdominal diaphragm still occur (Nelson et al 2015), and fascial weakness makes hernia more common (Nazeem et al 2013). 

Hypermobile Ehlers-Danlos Syndrome As A Risk Factor For Small Fiber Neuropathy

Neuropathic pain is common in hEDS with clear subjective descriptions without objective neuropathic causes. However, Cazzato et al (2016) found small fiber neuropathy may be the cause of these symptoms. 

Increased vulnerability is linked to underlying genetic defects in TNXB, collagens I, III, or V making up the endoneurium, epineurium, perineurium of nerves (Voermans et al 2009, Granata et al 2013]. Subluxations and increased mobility in the joints may further exacerbate this situation. This may explain at least in part the increase incidence of axonal polyneuropathy in various types of EDS (Muellbacher et al 1998).

Indeed it may be these changes that give rise to many of the associated symptoms in hEDS. As shown by Levine (2018) in figure 1 small fibre neuropathy is capable of causing the majority of symptoms attributed to hEDS and chronic overlapping pain syndromes. 

Diagnosis of Hypermobility Ehlers Danlos Syndrome

hEDS has an autosomal inheritance and unknown molecular basis.

The clinical diagnosis of hEDS needs the simultaneous presence of criteria 1 AND 2 AND 3.

Criterion 1: Generalized Joint Hypermobility (GJH)

Beighton score GJH is ≥5 points out of 9.

The Committee on behalf of the International Consortium on the Ehlers–Danlos Syndromes (Malfait et al 2017) proposes ≥6 for pre‐pubertal children and adolescents, ≥5 for pubertal men and women up to the age of 50, and ≥4 for those >50 years of age for hEDS.

If the Beighton score is 1 point below the age‐ and sex‐specific cut‐off AND the 5PQ is ‘positive’ (= at least two positive items), then a diagnosis of GJH can be made.

Table III. The Five‐Point Questionnaire. Adapted From [Grahame and Hakim, 2003]

1. Can you now (or could you ever) place your hands flat on the floor without bending your knees?
2. Can you now (or could you ever) bend your thumb to touch your forearm?
3. As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits?
4. As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion?
5. Do you consider yourself “double‐jointed”?


Criterion 2: Two or More Among the Following Features (A–C) MUST Be Present

Feature A:

Systemic manifestations of a more generalized connective tissue disorder (a total of five must be present)

1. Unusually soft or velvety skin

2. Mild skin hyperextensibility

3. Unexplained striae such as striae distensae or rubrae at the back, groins, thighs, breasts and/or abdomen in adolescents, men or prepubertal women without a history of significant gain or loss of body fat or weight

4. Bilateral piezogenic papules of the heel

5. Recurrent or multiple abdominal hernia(s) (e.g., umbilical, inguinal, crural)

6. Atrophic scarring involving at least two sites and without the formation of truly papyraceous and/or hemosideric scars as seen in classical EDS

7. Pelvic floor, rectal, and/or uterine prolapse in children, men or nulliparous women without a history of morbid obesity or other known predisposing medical condition

8. Dental crowding and high or narrow palate

9. Arachnodactyly, as defined in one or more of the following: (i) positive wrist sign (Steinberg sign) on both sides; (ii) positive thumb sign (Walker sign) on both sides

10. Arm span‐to‐height ≥1.05

11. Mitral valve prolapse (MVP) mild or greater based on strict echocardiographic criteria

12. Aortic root dilatation with Z‐score > +2

Feature B:

Positive family history, with one or more first degree relatives independently meeting the current diagnostic criteria for hEDS.

Feature C:

Musculoskeletal complications (must have at least one)

1. Musculoskeletal pain in two or more limbs, recurring daily for at least 3 months

2. Chronic, widespread pain for ≥3 months

3. Recurrent joint dislocations or frank joint instability, in the absence of trauma (a or b)

a. Three or more atraumatic dislocations in the same joint or two or more atraumatic dislocations in two different joints occurring at different times

b. Medical confirmation of joint instability at two or more sites not related to trauma

Criterion 3: All the Following Prerequisites MUST Be Met

1. Absence of unusual skin fragility, which should prompt consideration of other types of EDS.

2. Exclusion of other heritable and acquired connective tissue disorders, including autoimmune rheumatologic conditions. In patients with an acquired connective tissue disorder (e.g., lupus, rheumatoid arthritis, etc.), additional diagnosis of hEDS requires meeting both Features A and B of Criterion 2.

Feature C of Criterion 2 (chronic pain and/or instability) cannot be counted towards a diagnosis of hEDS in this situation. 3. Exclusion of alternative diagnoses that may also include joint hypermobility by means of hypotonia and/or connective tissue laxity. Alternative diagnoses and diagnostic categories include, but are not limited to, neuromuscular disorders (e.g., myopathic EDS, Bethlem myopathy), other HCTD (e.g., other types of EDS, Loeys–Dietz syndrome, Marfan syndrome), and skeletal dysplasias (e.g., OI). Exclusion of these considerations may be based upon history, physical examination, and/or molecular genetic testing, as indicated.

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