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REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
12
VOLUME 12 NUMBER 1 • JULY 2015
Stem cell therapies for neuropathic pain
JASON SEEWOODHARY, JOHN N HARVEY
Correspondence to: Dr Jason Seewoodhary
Department of Diabetes Mellitus and Endocrinology, Wrexham Maelor
Hospital, Croesnewydd Road, Wrexham, LL13 7TD, UK.
Tel: +44 (0)7908 070455
E-mail:
seewoodharyj@hotmail.comPreviously published in
Br J Diabetes Vasc Dis
2014;
14
: 2–9
S Afr J Diabetes Vasc Dis
2015;
12
: 12–18
Abstract
Neuropathic pain is a large-scale epidemiological problem
effecting 13–26% of the diabetic population. The complex
aetiology and pathophysiology coupled with the lack of
a diagnostic test for the underlying cause renders the
assessment of neuropathic pain subjective and the treatment
difficult, especially as current licensed treatments are limited
in their application towards the attainment of palliation.
Cell therapies offer a novel curative therapeutic dimension
for neuropathic pain. This is based on replacing damaged
neuronal tissue, protecting against progressive nerve
damage, and releasing soluble factors that act in a paracrine
or endocrine manner, which facilitate repair and reversal of
the pathology that underlies the genesis and propagation
of damage within the somatosensory system. Cell therapies
with potential utility for the treatment of neuropathic pain
include embryonic stem cells, adult stem cells and induced
pluripotent stem cells.
Keywords:
stem cell, neuropathic pain, cell therapy, regeneration,
analgesia, diabetes
Introduction
Current licensed therapies for the treatment of neuropathic pain are
limited in their application towards the attainment of palliation. They
are not disease modifying or neuroprotective, being incapable of
reversing or repairing the pathology that underlies the genesis and
propagation of damage within the somatosensory system. Stem cells
may offer a novel curative regenerative therapeutic dimension. This
review will discuss the potential utility of stem cells for the treatment
of neuropathic pain.
Neuropathic pain
Neuropathic pain is a subtype of pain defined by IASP as “pain
arising as a direct consequence of a lesion or disease affecting the
somatosensory system”. The predominant symptom is paroxysmal
episodes of stabbing or shooting pain arising in an area of hyper-
excitability or numbness. Other symptoms include: spontaneous
pain, hyperalgesia and allodynia; dyaesthesias; abnormal thermal
sensations; and deep-seated gnawing pain.
Epidemiology
Neuropathic pain is a large-scale problem; epidemiological data
estimate neuropathic pain affects 13–26% of diabetic patients.
1
However, due to the complex aetiology of neuropathic pain coupled
with the lack of a diagnostic test and standardised measurement
methods, exact data are deficient, which renders the overall
prevalence difficult to quantify. Accordingly the health economic
costs of neuropathic pain to society are undetermined.
Aetiology and pathophysiology
The aetiology of neuropathic pain can be categorised morpho-
logically into four groups: peripheral nervous system and multi-focal
lesions e.g. diabetic mononeuropathy; peripheral nervous system
generalised polyneuropathies e.g. alcohol-related neuropathy;
central nervous system lesions e.g. spinal cord injury; and complex
neuropathic disorders, such as complex regional pain syndrome
types I and II.
2
However, this classification system is not universally
accepted.
The pathophysiology of neuropathic pain is complex and results
from several processes, which cumulatively lead to peripheral
and central sensitisation associated with ectopic activity and
hyperexcitability in pain pathways.
3
This is associated with
histopathological changes within affected nerves characterised by:
Wallerian degeneration; sprouting; formation of end-neuromas
and neuromas-in-continuity; and compression induced atrophy.
4
Peripheral mechanisms act on nociceptors. The hyperactivity in
nociceptors induces hyperexcitability in the spinal cord and brain,
referred to as central sensitisation. A schematic depicting the
various alterations in nerve function leading to neuropathic pain is
illustrated in Fig. 1.
Diagnosis and treatment
Neuropathic pain is diagnosed clinically. Screening methods are
based on questionnaires such as the Leeds Assessment of Neu-
ropathic Symptoms and Signs or the pain DETECT questionnaire.
The Neuropathic Pain Special Interest Group of the IASP has
developed evidence-based guidelines for the pharmacological
treatment of neuropathic pain.
5
Based on the results of randomised
controlled trials, first-line agents include: tricyclic anti-depressants,
selective serotonin and noradrenaline reuptake inhibitors, voltage-
gated Ca
2
+ channel
α
2-
δ
ligands, and topical local anaesthetics.
Second-line medicines include opioid analgesics and tramadol.
Third-line drugs include valproate, topiramate, mexiletine and
topical capsaicin.
6
Non-pharmacological treatments include: surgical and chemical
sympathectomy, which are limited in their application by a sparse
evidence base and considerable complications;
7
neurodestructive
procedures, which are hindered by a risk of exacerbating symptoma-
tology; neurostimulation e.g. transcutaneous electrical nerve stimu-
lation, although this is not based on conclusive evidence;
8
spinal cord
stimulation; acupuncture; and cognitive behavioural therapy.
Limitations of current treatment
Therefore, the management of neuropathic pain is challenging
with a poor prognosis. Treatment is hindered for a number of
reasons: there is no definitive corroboration between published