Neuropathic pain

1. Neuropathic pain Roger McFadden 2007

2. Nociceptors These are pain sensing nerve endings found at the distal end of afferent pain neurons - often called nociceptive neurons. � Nociceptors are divided into two broad categories� High threshold mechanoceptors that respond to mechanical stimulation that send pain signals to the CNS via myelinated Ad type neurons. These respond to crushing and pinching type stimuli but at relatively high levels - otherwise normal pressure would initiate pain responses. �

3. Nociceptors Polymodal nociceptors that respond to thermal, chemical and mechanical stimulation that send pain signals to the CNS via unmyelinated C type neurons. Classes of nociceptive neurons� Ad type neurons are myelinated and transmit information at relatively high speeds between 5 - 25 m sec-1. These generally transmit sharp, well localised pain. � C type neurons are unmyelinated and transmit information at relatively low speeds between 1 - 2 m sec-1. These generally transmit dull, burning pain that is less well localised. �

4. Neurotransmitters and modulators The neurotransmitter glutamate mediates fast transmission in nociceptor pathways via its action on NMDA* receptors. � There are many other local neuromodulators involved in nociceptive transmission such as the tachykinins that include Substance P and also neurokinin A. The action of these neuromodulators is complex and by no means fully characterised. * NMDA - N-methyl-D-aspartate

5. Pain transmission The two main tracts for pain transmission are spinothalamic tracts and spinoreticular tracts � Spinothalamic tracts that ascend to the thalamus and from there to the frontal cortex where the pain is interpreted and the somatosensory cortex where it is localised

6. Pain transmission Spinothalamic pain pathway

7. Pain transmission Spinoreticular tracts ascend via the reticular formation in the brain stem.  Here, third order neurons convey the pain stimuli to the thalamus and to various areas of the cortex.  It is thought that this pathway is responsible for conveying the dull, aching type of pain and also for stimulating some of the sympathetic responses associated with pain

8. Pain transmission Spinoreticular tracts

9. Nociceptive & Neuropathic pain Pain is broadly divided into two types - nociceptive pain and neuropathic pain Nociceptive pain � injury, disease or infection that results in the stimulation of nociceptive neurons that transmit pain signals into the CNS Neuropathic pain - caused by neurological dysfunction that results in the perception of pain

10. Neuropathic pain Various conditions can affect nerves and these can cause neuropathic pain as a consequence of the problem. These include the following� Trigeminal neuralgia. Post herpetic neuralgia (pain following shingles). Phantom limb pain after an amputation. Multiple sclerosis. Pain from chemotherapy. HIV infection. Cancer Diabetic neuropathy

11. Neuropathic pain - manifestations Hyperalgesia - severe pain from a stimulus that would normally cause only slight discomfort Paresthesia - unpleasant or painful feelings e.g. pins and needles with no apparent stimulus Allodynia � pain from a stimulus that would not normally cause pain Symptoms such as depression and anxiety may result from neuropathic pain

12. The action potential

13. The action potential

14. Neuropathic pain � pathology I Nerve damage may result in an over-expression of Na+ channels in the neurons of the damaged area An imbalance of Na+ and K+ ions may result in neurons becoming hyperexcitable This can result in the spontaneous generation of action potentials in nociceptive neurons The over-expression of Ca2+ channels in the afferents of the dorsal root ganglia may also be involved in neuropathic pain, explaining the action of calcium-channel antagonists such as gabapentin and pregabalin

15. Neuropathic pain � pathology II Sympathetically maintained pain may be due to neuronal growth in the afferents of the dorsal root ganglia Peripheral nerve injury may cause activation of various kinases and proteins, including enhanced N-methyl-D-aspartate (NMDA) receptor activity within the grey matter of the spinal cord Demyelination in multiple sclerosis may be another cause of increased nociceptive excitability

16. Neuropathic pain - treatment Analgesics such as paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), codeine etc. These are unpredictable in their efficacy against neuropathic pain Antidepressants such as the tricyclic, amitriptyline. These work by an action (poorly understood) separate to their action on depression. Anti-epileptic drugs such as gabapentin, pregabalin, carbamazepine and sodium valproate. These inhibit excitable neurons in epilepsy and have a similar action in neuropathic pain Capsaicin is the active ingredient in chill and desensitises nociceptive neurons and depletes them of substance P

17. End of Presentation