Friday, 17 June 2016

Controlling Spasticity

Pharmacological management of spasticity in multiple sclerosis: Systematic review and consensus paper.Otero-Romero S, Sastre-Garriga J, Comi G, Hartung HP, Soelberg Sørensen P, Thompson AJ, Vermersch P, Gold R, Montalban X. Scler. 2016  pii: 1352458516643600. [Epub ahead of print]

BACKGROUND AND OBJECTIVES:Treatment of spasticity poses a major challenge given the complex clinical presentation and variable efficacy and safety profiles of available drugs. We present a systematic review of the pharmacological treatment of spasticity in multiple sclerosis(MS) patients.
METHODS:Controlled trials and observational studies were identified. Scientific evidence was evaluated according to pre-specified levels of certainty.
RESULTS: The evidence supports the use of baclofen, tizanidine and gabapentin as first-line options. Diazepam or dantrolene could be considered if no clinical improvement is seen with the previous drugs. Nabiximols has a positive effect when used as add-on therapy in patients with poor response and/or tolerance to first-line oral treatments. Despite limited evidence, intrathecal baclofen and intrathecal phenol show a positive effect in severe spasticity and suboptimal response to oral drugs.
CONCLUSION:The available studies on spasticity treatment offer some insight to guide clinical practice but are of variable methodological quality. Large, well-designed trials are needed to confirm the effectiveness of anti-spasticity agents and to produce evidence-based treatment algorithms.


The anti-spastic agents are decades old and only Nabiximols is a modern era drug, so who is going to fund a large trial on any of these old drugs?

Answer is going to be no-one, as it will cost too much. 

However, to suggest that large trials are needed to confirm effectiveness is a somewhat worrying state of affairs. 

It suggests that the trial data is not sufficiently robust, which perhaps relates to trial design and if trial design is not well developed the chances of developing something new, is going to be harder.

However the biology is there to support their use.

Spasticity is caused by too much nerve excitment causing muscle contractions due to the nerve damage caused by MS. 

There exists a balance in nerve impulse transmission. Nerves can be excited and they can be inhibited by inhibitory nerves. So you can get too much excitation by excitation of the excitatory nerves or by too little inhibition of inhibitory nerves.



There is an exaggerated stretch response. (cross you legs, tap your leg just below the knee cap and your leg kicks.  That's the stretch response.

You feel the tap the nerve impulse travels to the spinal cord via sensory nerves, these nerves make synapses so the stimulation goes to the brain so you get the sensation of the tap. However, nerves in the spinal cord synapse (join) with motor (movement) nerves in spinal cord and the nerve impulse travels down to the motor nerve into the quadracep muscle and the muscle contracts. At the same time the nerve sensing the tap synapes with and stimulates an inhibitory nerve in the spinal to turn the motor nerve to the hamstring to relax. This allows the kick to occur. In MS because of nerve damage in the brain and the spinal cord the inhibitory signal that normally controls the strength of the strecth response is limited and so the signalls going to the motor nerves are amplified and causing contraction or a kung-fu kick.

In spasticity this response is exaggerated and can be sometimes measured.

Dantrolene acts in the muscles to block contraction. However, the muscle contractions are caused by over stimulation of the nerve tracts. Intrathecal phenol blocks the nerve stimulation

Tizanidine blocks the action of excitatory nerves as does nabiximols and stops nerve impulses crossing synapses, whereas GABApentin, baclofen and diazepam augment/mimic the inhibitory nerve signalling.

When a nerve impulse is transmitted it moves because of the action of sodium channels. The outside of the cell is normally more electrically positive than the inside of the cell.



So when the stimulus comes along sodium ions which are electricialy positive ,start to move into the cell to make the inside of the cell more electrically positive and the outside more negative and it moves along at sodium channels. Then there is a reset.
This is how the nerve impulse travels and it travels quicker with myelin because the impulse jumps along the nerve faster
 

The inside of the cell is about 60-70 thousandth of a volt less electrically positive or 60-70 thousandth more negative



When this difference between the outside and the inside of the cell is -55 thousands of a volt, voltage-gated sodium channels (sodium channels that respond to voltage) open and sodium ions rush into the nerve making the inside of the nerve positive. This is called DEPOLARISATION. This sets off the same reaction at the next sodium channel along the nerve (see above)
.

When the electrical difference between the inside and the outside is 30 to 40 thousandth of a volt more positive on inside the cell than the outside the sodium channels close. The system then resets itself with voltage gated potassium channels by potassium ions moving out of the cell. The potassium ions also carry a positive charge, so as they move out, the inside becomes more negative and the outside becomes more positive. This is called REPOLARIZATION. As the voltage difference between the outside and inside resets, the potassium channels close.

When the inside of the cell gets to the stage where the difference between the outside and inside of the cell is more than 60-70 thousandths of a volt and this is called HYPERPOLARISATION making it more difficult for the threshold, required to send the next nerve impulse by sodium channels, to be reached. This makes it more difficult for the nerve to be excited and so less likely that the nerve impulse is fired.
Then potassium is pumped in and sodium is pumped out (by the potassium sodium pump) and because three sodiums (+++) are pumped out for every two potassium (++) the outside becomes positive relative to the inside of the cell again.

The problem of spasticity is nerve impulses are being fired too frequently and the solution is to hyperpolerize the nerves to stop them firing so often.
GABApentin and baclofen are thought to act via the same mechanism and stimulates the GABA(B) receptor, which stimulates signalling molecules that cause calcium channels to close so calcium ions (++) do not move into the cell when sodium ions (+) enters. Meaning it is more likely that the inside of the cell will not become positive. 

Importantly  the signalling molecules open an inwardly rectifying  potassium channels to open moving poassium outside the cell (in addition to that moving by the voltage gated potassium channels). This serves to make the inside of the nerve cell to become more electrically negative and so it becomes hyperpolarised and so nerve impulses are less likely to be fired. 


Nabiximols acts via the cannabinoid receptor and this stimulates similar signalling molecules activated by the GABA(B) receptor and again closes calcium channels and opens the inwardly rectifying potassium channel making the inside of the cell more negative as potisive potassium ions leaving the cell. Again hyperpolarising the nerve.


Diazepam acts because it stimulates the GABA(A) receptor this means that a channel that allows chloride ions to enter the cell. Chloride ions are negatively charged and so make the inside of the cell more negative.

Therefore most of the anti-spastic drugs have a common mechanism of action and hyperploarise nerves to limit excessive nerve impulse firing.

Their problem is that nerve firing is part of life. These inhibitory pathways can effect essentially any nerve pathway and so not only block the excessive nerve signalling that controls spasticity but also inhibit normal nerve signalling and so they can inhibit movement and cognitive function and cause sedation.

If you could do this  in a more disease related way you may be able to control spasticity but not trigger sedation.

Impossible? We shall see.

COI: We are developing a treatment for spasticity.

6 comments:

  1. WOW! What a fantastic article MouseDoc!

    Thank you so much!

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    1. I was just about to write something similar... thanks for the entry!!

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  2. This has stolen my thunder a bit for my talk tomorrow but there's still a bit more to be revealed for those who are attending ;-)

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    1. I am just down the street in Rochester NY. I dont think I can make it.

      I've never flown actually. Before my MS I might have been able to if my co-pilot was Cap'n Valium. When I was young, fearless. I drag raced, was an equestrian barrel racing and then some champion. I was then struck with Meningitis w/ back curvature. Was told by the time I was 25 I'd be in a wheelchair, by 35 probably no longer here.

      I was fitted for a full body brace to try keep me straight. A short time before final fitting and having it assembled on me I was in my parents tub. Was crying me eyes out, praying, I wanted to die. Seriously. I wont tell you what I did.

      But the day arrived, I went in. Nothing fit. So the team scrambled around checking this, measuring that. I and my parents had no real idea why they appeared so frantic. We just figured they messed up.

      I was sent back for a new series of tests and it was gone. Presto. They asked me and my parents all sorts of questions. I told them what I did. Anyways, was classified a medical miracle.

      Since that point however I'd started getting anxiety.

      When I was hit with MS in my 40's it got worse.

      If I were to try fly now and you were in the cabin you'd be saying, "Who's the crazy chick trying to open the door before we ever get off the ground?" That'd be me :)

      I cant do highways... I have to know how to get someplace in advance... I've had to learn to manage stress or it manifests back to anxiety.

      But I CAN be there in spirit!

      I am confident you will knock it out of the park!

      Would love to see more articles like this educational!

      Learning is Fun-Da-Mental!

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  3. Brilliant! I was a fan of the old MD, but I love this new version. What a great post. Where's this crowd funding so I can support more of this?! Thanks.

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