Why has neuropathic pain proven difficult to treat pharmacologically?
Intro - what is neuropathic pain - it is pain spontaneously generated in somatosensory
nerves as a result of some sort of trauma to nerve for a variety of reasons such as
mechanical injury, infection, tumour invasion etc… Due to the wide variety of types of
neuropathic pain, and the cause being not well understood, it has been difficult to
pharmacologically treat neuropathic pain, with many patients' pain not being effectively
managed despite trying many different therapeutics. Using antidepressants as the first line
therapy for neuropathic pain to show why it is difficult to treat due to a lack of understanding
around the causes of the condition this essay will explore why neuropathic pain has proven
difficult to treat pharmacologically.
Mechanism of neuropathic pain development -
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371025/#:~:text=Neuropathic%20pain%20is
%20caused%20by,10%25%20of%20the%20general%20population.
- There are multiple causes of neuropathic pain, and many factors that contribute to its
development such as chemotherapy, diabetes and mechanical injury which all lead to
nerve damage (Colloca et al, 2017).
- Khan et al, 2002 - increase in spontaneous activity in rats with induced diabetic
neuropathy in all types of nerve fibre, but significantly in Adelta and beta fibres. Using
Resiniferatoxin to desensitise the classically nociceptive C fibres in the rats, they
found that this did not affect the development of diabetic neuropathy induced
neuropathic pain in the rats which suggested that abnormal sensory input from Aδ-
and Aβ-fiber afferents likely is involved in the development of diabetic neuropathic
pain. - it is possible that this extends to other forms of neuropathic pain.
- The cause of spontaneous nerve firing in neuropathic pain is not very well
understood. Suggestions that it was due to NaV 1.7/1.8 activity were shown to be
wrong as NaV1.7/8 DRG KO mice develop neuropathic pain as normal (Kerr et al,
2001, Minett et al, 2012), so these ion channels in nociceptors are not necessary to
mediate neuropathic pain,
- It was found by Minett et al, 2014, that in DRG and sympathetic neuron
NaV1.7KO mice, neuropathic pain does not develop normally, and is
abolished - this study used 3 models of neuropathic pain, the spinal nerve
transection model (neuropathic pain due to mechanical injury), chronic
constriction injury model (mimics neuropathic pain due to an immune
response and neuritis) and an oxaliplatin model (mimic chemo induced
neuropathic pain). They found that chronic constriction neuropathic pain is
dependent on NaV1.7 expression while the other two models were not
dependent on its expression - they did not use a streptozotocin induced mice
neuropathy model which mimics diabetic neuropathy, so the effects of NaV1.7
expression in this mouse model wasn't taken into account - different
mechanisms underlying neuropathic pain depending on the cause, makes it
difficult to treat as the underlying cause is variable.
- This study also implicated the sensory neurons in the development of
neuropathic pain again, reinforcing the findings from Khan et als study in
which inhibition of the nociceptive C fibres still allowed for diabetic
Intro - what is neuropathic pain - it is pain spontaneously generated in somatosensory
nerves as a result of some sort of trauma to nerve for a variety of reasons such as
mechanical injury, infection, tumour invasion etc… Due to the wide variety of types of
neuropathic pain, and the cause being not well understood, it has been difficult to
pharmacologically treat neuropathic pain, with many patients' pain not being effectively
managed despite trying many different therapeutics. Using antidepressants as the first line
therapy for neuropathic pain to show why it is difficult to treat due to a lack of understanding
around the causes of the condition this essay will explore why neuropathic pain has proven
difficult to treat pharmacologically.
Mechanism of neuropathic pain development -
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371025/#:~:text=Neuropathic%20pain%20is
%20caused%20by,10%25%20of%20the%20general%20population.
- There are multiple causes of neuropathic pain, and many factors that contribute to its
development such as chemotherapy, diabetes and mechanical injury which all lead to
nerve damage (Colloca et al, 2017).
- Khan et al, 2002 - increase in spontaneous activity in rats with induced diabetic
neuropathy in all types of nerve fibre, but significantly in Adelta and beta fibres. Using
Resiniferatoxin to desensitise the classically nociceptive C fibres in the rats, they
found that this did not affect the development of diabetic neuropathy induced
neuropathic pain in the rats which suggested that abnormal sensory input from Aδ-
and Aβ-fiber afferents likely is involved in the development of diabetic neuropathic
pain. - it is possible that this extends to other forms of neuropathic pain.
- The cause of spontaneous nerve firing in neuropathic pain is not very well
understood. Suggestions that it was due to NaV 1.7/1.8 activity were shown to be
wrong as NaV1.7/8 DRG KO mice develop neuropathic pain as normal (Kerr et al,
2001, Minett et al, 2012), so these ion channels in nociceptors are not necessary to
mediate neuropathic pain,
- It was found by Minett et al, 2014, that in DRG and sympathetic neuron
NaV1.7KO mice, neuropathic pain does not develop normally, and is
abolished - this study used 3 models of neuropathic pain, the spinal nerve
transection model (neuropathic pain due to mechanical injury), chronic
constriction injury model (mimics neuropathic pain due to an immune
response and neuritis) and an oxaliplatin model (mimic chemo induced
neuropathic pain). They found that chronic constriction neuropathic pain is
dependent on NaV1.7 expression while the other two models were not
dependent on its expression - they did not use a streptozotocin induced mice
neuropathy model which mimics diabetic neuropathy, so the effects of NaV1.7
expression in this mouse model wasn't taken into account - different
mechanisms underlying neuropathic pain depending on the cause, makes it
difficult to treat as the underlying cause is variable.
- This study also implicated the sensory neurons in the development of
neuropathic pain again, reinforcing the findings from Khan et als study in
which inhibition of the nociceptive C fibres still allowed for diabetic
