Case study: are you a zombie because of your spasticity medications?

Are you battling to get your nocturnal spasms under control? Are your legs collapsing when you increase the dose of your anti-spastic medication?

Case study

I am 48 years old and have secondary progressive MS. In the past, I was treated with natalizumab, fingolimod and cladribine and have not had any DMTs for close to three years. I am only just walking; I can manage about 10 metres with a walking frame. I have weak legs and dropped feet, which causes frequent falls. I have tried using functional electrical stimulators in the past and have to revert to using foot splints. My biggest problem is spasticity and severe leg spasms in the early hours of the morning and when I get up in the morning. I am on Gabapentin 900mg three times a day and Baclofen 60mg a day. I take 30mg of Baclofen at about 10 pm just before going to bed at night, 10mg at 8 am and 20mg at about 2 pm. I am using 2mg of Clonazepam at night and have also started using Sativex 2-3 puffs at night. If I take Sativex in the day I feel very confused and battle to stand. Sativex also reduces my truncal tone so that I can’t sit up straight in my wheelchair. I tend to slouch to the right. My biggest problem, however, is my cognition. I spend most of my time during the day struggling to stay awake. I am still working as a part-time legal advisor, but I am finding it increasingly difficult to work.

Can you please advise? 

Photo by Ephraim Mayrena on Unsplash

Prof G’s opinion

This person has advanced MS and seems to be close to becoming wheelchairbound. He has spastic paraparesis with severe spasticity. I am not surprised he is struggling to stay awake in the day; he is on such large doses of antispasticity medication. 

He describes early morning spasms that wake him up from sleep. This is typical of spasticity, in general, but is also because the half-life of baclofen and possibly gabapentin are too short to last the whole night. Baclofen has a half-life of about 4-6 hours and a very narrow therapeutic window. This means that it does not last long enough to keep his spasticity under control for the whole night. Pharma has been trying to develop a slow-release form of baclofen for decades, but it is a tricky drug to work with, hence no slow-release baclofen. One option for this pwMS is to set an alarm to wake up at 2-3 am to take another dose of baclofen. Would you do that? 

Gabapentin has a longer half-life of 5-7 hours and some people need to take it every 6 hours, or fours times a day, to get full coverage of its antispasticity effects. This would be something to try, i.e. add in another dose of gabapentin and try to space out the doses so that there is 24-hour coverage of its antispastic effects. Please note this is an increase in dose and hence will do nothing for his daytime tiredness and will likely make it worse. However, as he is not getting a good night’s sleep this strategy may improve his wakefulness in the day because of improved sleep hygiene. 

Clonazepam, is a benzodiazepine, with a long half-life of over 20 hours. This is why it is so sedating during the day. I would not increase the dose of clonazepam for this reason as it is likely to worsen the lower limb and truncal weakness.

Sativex is a cannabinoid and combines THC, the likely active ingredient that works against spasticity, with low dose CBD. Unfortunately, THC the active ingredient has no therapeutic window; the level that reduces spasticity is also the level that has psychoactive effects and some pwMS don’t like the dysphoria/euphoria that goes with it. Please note that only about 1 in 3 pwMS with MS-related spasticity respond to Sativex. The one advantage that Sativex and other CB1 agonists have is that they improve nighttime limb jerks and limb spasms and hence improve sleep. So one option would be to gradually increase the dose of Sativex this patient is taking. I see no reason why he should not increase his number of puffs to 6 or even 8 at night. The one downside of doing this is that it will cause the ragdoll effect or weakness and this may impact him being able to go to the toilet or using a commode at night on his own. 

I have found that many of my patients who use street cannabis for pain and spasticity tend to use it at night to improve their symptoms when they are at their worst and to help them get a good nights sleep. Although the medicinal use of cannabis has been legalised in the UK there is no mechanism for NHS staff to prescribe it at present. Patients either have to go to private cannabis clinics or source it themselves on the street. I don’t like them doing the latter as there is no way of controlling the quality of the cannabis; THC concentrations vary widely between different strains of the cannabis plant and even between batches of the same strain. The same applies to purchasing hashish on the web from suppliers in Amsterdam. This is why we desperately need an NHS quality approved formulation of medicinal cannabis so we can prescribe it instead of having our patients sourcing it themselves. 

We do have another medicinal equivalent of THC called Nabilone. Nabilone is a licensed small molecule CB1 agonist which works on the same receptor as THC. Nabilone is licensed for the control of nausea and vomiting, caused by chemotherapeutic agents used in the treatment of cancer, in patients who have failed to respond adequately to conventional antiemetic treatments. In my experience, it works very well in some patients with MS-related spasticity, particularly when it is associated with pain. Nabilone has a half-life in terms of its effect on spasticity of between 5-10 hours, i.e. it is quite variable so some patients get away with twice a day dosing and others need to take it three times a day. As with Sativex, no all patients respond and it causes the same dysphoria and sedation. I can’t see Nabilone making any difference to this patient’s current management of spasticity. 

This pwMS also needs a detailed assement to make sure there are no exacerbating factors that can make spasticity worse; urinary tract infection, faecal impaction, a pressure sore or poorly fitting shoes or splints. 

Please note that the rag-doll effect occurs in pwMS who are very weak in their legs and essentially need spasticity or tone to use them as splints to walk. Take away the spasticity and the extent of the leg weakness is exposed and they collapse like those of a ragdoll. This makes it very difficult to manage spasticity and spasms. In the future when the technology matures we may be able to use exoskeletons in this situation; i.e. to strap on biomechanical walking devices that are able to support the patient even if they have leg weakness. The exoskeleton technology is evolving rapidly and being trialled in paraplegics in the UK. They are available already for pwMS privately. I saw a patient advocate walking with an exoskeleton at an MS meeting I attended in Germany before the COVID-19 pandemic; it was remarkable to see how well he walked. 

To be honest this patient faces a harsh choice. If he wants to get his spasticity under control and at the same time reduce his daytime sedation he will have to accept that he will need to probably give up walking. If he is prepared to accept this compromise I would refer them for an intrathecal baclofen pump assessment. The beauty of a baclofen pump is that delivers the baclofen directly into the spinal fluid around the spinal cord, i.e. to where it is needed. This will allow hime to probably withdraw all his other medication and hence have a clear head, which will allow him to continue to work in the day.  

At the moment he is spending most of his day as a zombie from all the heavy sedating medication he is on. The only way to get rid of the daytime sedation and treat the spasticity is to use intrathecal baclofen. 

Some of you will ask what about other antispastic agents, i.e. tizanidine and dantrolene. These are not a solution. Tizanidine will increase his sedation and both will make his weakness worse. He is already on four antispastic agents (baclofen, gabapentin, clonazepam and Sativex) adding on a fifth and sixth agent doesn’t make sense. What about swapping out one he is on already for say Tizanidine? Yes, but this won’t deal with the conflicting problems of (1) spasticity/spasm vs. (2) ragdoll effect and being unable to walk vs. (3) excessive sedation and cognitive problems with difficult working. My advice would be to give up on the walking in anticipation of a future exoskeleton and to get the spasticity under control and so as to clear his head to allow him to continue working. What is not mentioned in the case history above is that this person needs an income; he is married and has a relatively young family to help support.  

My suggestions:

1. To wake up at 2-3 am to take another dose of baclofen

2. Add another dose of gabapentin, i.e. to take it four times rather than three times a day

3. To gradually increase the nighttime dose of Sativex provided the pwMS doesn’t need to walk during the night

4. To refer for a trial of intrathecal baclofen

This pwMS also needs to be referred for physiotherapy as well. Sometimes exercise and a stretching programme can improve spasticity. Another factor is falls prevention. This pwMS needs to have a bone density or DEXA scan as part of a fracture prevention programme, i.e. to make sure they are not osteopaenic or osteoporotic. 

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.