“ Surge Protector“ is a great analogy for these kinds of medications, which keep me from blowing my fuses.
Producing a sensation of pain is a complex operation:
- From the pain signals produced at the site of an injury,
- to the peripheral nerves that transmit those signals,
- to the dorsal root ganglia that filters them,
- to the spinal cord and then up
- to the brain,
The production of the pain involves many factors – each of which could conceivably be targeted to reduce pain.
This blog uses a Pain Research Forum webinar“Targeting Unusual Voltage-Gated Sodium Currents for Pain Therapy” to check out work that’s targeting one of the first players on the scene – the sodium channels in the sensory nerves that start the process of producing pain in the body.
Ted Cummings, a pain researcher, wants to turn off the most basic aspect of pain production – the increased electrical activity in the sensory nerves which causes them to shoot pain signals to the brain.
That means focusing on the”voltage-gated sodium channels” that litter pain- producing neurons.
When these sodium channels open sodium floods into the cell, causing it to generate an electrical charge – which sends a pain signal zinging up the nerves to the brain.
Nine different types of sodium channels exist. If you’re interested in targets for pain then three types of sodium channels (Nav 1.7, 1.8, 1.9) jump out.
Nav 1.7 sodium channels have been the best studied, but Nav 1.8 and 1.9 sodium channels may provide the best target. The goal in drug development is to find a target that only applies to pain. The Nav 1.8 and 1.9 sodium channels mostly meet this criterion both mostly found only in the periphery in pain-sensing neurons.
The Arizona Bark Scorpion’s sting has been described as having a burning cigarette ground into your arm and then a nail pounded through it.
The Bark Scorpion’s sting can kill lab mice but has no effect on the desert mouse that eats scorpions like candy.
Studies indicate that a scorpion’s bite turns or excites the pain nerves in laboratory mice but actually deadens them in the desert mouse.
The more the desert mouse is stung – the more impervious to pain it gets.
The scorpion’s sting is an analgesic – an opiate – for desert mice.
The ion channels that it either turned on or shut down depending on which mouse was stung were the Nav 1.8 channels.
Nav 1.7 ion channels also clearly associated with pain. They’re found primarily in nodules (the dorsal root ganglia (DRG)) found outside the spinal cord that filter sensory signals from the body from the body.
Mutations in these ion channel genes allow the ion channels to open more easily – allowing them to translate small amounts of stimuli such as touch into pain. Sound familiar?
In 2012, Dr. Martinez-Lavin found that a mutation in Nav. 1.7 genes was associated with severe fibromyalgia.
Resurgent Electrical Impulses – Resurgent Pain Production
These sodium channels usually become activated and then quickly become inactivated and enter into a quiescent phase.
A close study of them however, indicated that in chronic pain these ion channels “resurge” or open up during the inactive period and start dumping sodium back into the cell.
This inability to fully turn off the electrical signal produces an always “on” or hyper-excitable pain response.
Cumming’s believes these resurgent currents are intimately involved in producing chronic pain.
a wide variety of pain producing factors including inflammatory mediators and many biological toxins (wasp, scorpion, sea anemone toxins) induce these sodium ion channels to produce resurgent electrical currents; i.e. ongoing pain.
The big question is whether a drug can be developed to turn this resurgent electrical off.
Cummin’s reported that he’d found a particular genetic target called NavB4 which is able to stop some ion channels from resurging.
Now the question becomes how to produce a drug that can activate that genetic unit.
some drugs already on the market can stop this resurgence of electrical activity. All the drugs identified thus far appear to stop the resurgence in different ways.
Dr. Christine Sang noted that several anti-epileptic drugs effected sodium channels.
At the end of this post, I’ve included a brief explanation of how anticonvulsants/antiepileptics work on the nervous system, plus a surprisingly long list of drug-types in this single category.
Cannabidiol and Lidocaine can jam up the sodium channels and stop them from activating again.
A review of the recent literature found that several drugs have been identified:
- A congener of Sumatriptan, a migraine drug knocked down Nav1.7 ion channel activity
- The anti-arrhythmic drug Mexiletine knocked down Nav1.7 activity.
- Rufinamide stabilized sodium channel activity in mice with neuropathic pain.
- Lacosamide, a sodium channel blocker, is being tested in patients with a kind of small fiber neuropathy associated with sodium channel problems.
- A synthetic cannabinoid called ajulemic acid derived from THC (but which does not produce a high) inhibited the activity of all forms (Nav1.2-1.8) of sodium channels tested.
- An ongoing study will determine whether carbamazepine improves brain functioning in erythromelalgia patients with sodium channel problems. Carbamazepine is currently used mostly in epilepsy and neuropathic pain.
Genentech is working on a new class of small molecules that will lock sodium ion channels in their quiescent phase period which occurs directly after activation.
This is a very useful approach because it turns off ion channels when they’re active and causing problems but allows them to become active again when appropriate.
That obviates a concern that sodium channel blocking drugs could turn off pain signals entirely – causing patients to injure themselves unknowingly.
multiple companies were working on Nav1.7 ion channel blockers
Sodium channel gene mutations (SCN9A) were recently associated with dysautonomia and one type of small fiber neuropathy. A very large study (1500 people) will soon begin to assess the role genetic mutations in sodium channel genes play in producing chronic pain
Old drugs present the best possibilities for people in pain now.
The problem isn’t with the drugs, but with how they are used.
New sodium channel affecting drugs don’t appear to be a year or two years off but five or more years off.
If they say “five or more”, it will undoubtedly be far more than five years, so let’s not get too hopeful.
The good news is that drug companies recognize the enormous dividends that will befall any company able to deliver a good pain drug, and they appear to be investing heavily in sodium channel drugs.
Eventually, these new drugs will be manufactured and sold by the usual profit-motivated corporations, and will be priced outrageously so only wealthy patients can afford them.
“Effective pain management is a moral imperative –
one we are not meeting.”
from an IOM report
Anticonvulsant = Anti-epileptic (from Wikipedia)
Anticonvulsants are also increasingly being used in the treatment of bipolar disorder and borderline personality disorder, since many seem to act as mood stabilizers, and for the treatment of neuropathic pain.
Anticonvulsants suppress the rapid and excessive firing of neurons during seizures.
Conventional antiepileptic drugs may block sodium channels or enhance γ-aminobutyric acid (GABA) function
By blocking sodium or calcium channels, antiepileptic drugs reduce the release of excitatory glutamate, whose release is considered to be elevated in epilepsy
- 2.1 Aldehydes
- 2.2 Aromatic allylic alcohols
- 2.3 Barbiturates
- 2.4 Benzodiazepines
- 2.5 Bromides
- 2.6 Carbamates
- 2.7 Carboxamides
- 2.8 Fatty acids
- 2.9 Fructose derivatives
- 2.10 GABA analogs
- 2.11 Hydantoins
- 2.12 Oxazolidinediones
- 2.13 Propionates
- 2.14 Pyrimidinediones
- 2.15 Pyrrolidines
- 2.16 Succinimides
- 2.17 Sulfonamides
- 2.18 Triazines
- 2.19 Ureas
- 2.20 Valproylamides (amide derivatives of valproate)
- 2.21 Other
“ Surge Protectors“ is a great analogy for these kinds of medications, which I’ve been taking for years. They keep me from blowing my fuses :-)