Medical Practice

Understanding the practical aspects of cannabidiol (CBD) and tetrahydrocannabinol (THC)

 

Virginia Thornley, M.D., Board-certified Neurologist, Epileptologist

@VThornleyMD

July 15, 2018

Introduction 

This serves as medical information for educational purposes only not medical advice. Please consult with your treating  physician.

In contrast to the rest of the blog which is more scientific, this gives more practical information in the day to day workings of recommending medical cannabis. It gives the behind the scenes processes that happens before a patient can even begin to start their medical product. It is not a magic pill but because it is unlawful in Florida, a physician cannot even write it on a prescription pad. It takes one hour or more to evaluate, counsel and go over the registration process when presenting for the first time to a doctor.

For more detailed information and scientific references for specific indications please refer to
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Medical cannabis is one of the most misunderstood and controversial medications in the world. Long suppressed for over a century, it is one of the most misunderstood medications known to mankind despite being used for thousands of years with medical intent.

This is to give a brief basic background of mechanisms, rationale for ratios, combinations, pitfalls of isolates and synthetics and legal implications.

Background

The endocannabinoid system is found naturally in our body. It is responsible for the runner’s high people get. It gives a sense of wellbeing, not endorphins like most people think, those molecules are too large to pass the blood-brain-barrier. There are 2 receptors:(1) the CB1 receptor found mostly in the nervous system and (2) the CB2 receptor which is more abundantly found in the immune system. Anandamide works on the CB1 receptor, tetrahydrocannabinol (THC) is similar to this and works on the CB1 receptor. CBD or cannabidiol is from the cannabis sativa plant and is also a phytocannabinoid. One needs 100 times the CBD to get the euphoria as THC. CBD is not intoxicating, legal and works on a wide variety of symptoms including pain, seizures and anxiety. CBD is similar to 2-arachidonoyl glycerol which is a natural cannabinoid. When the 2 are combined together, CBD will offset side effects of THC including paranoia, hyperactivity and agitation. This is a not known fact to those who self-medicate with pure THC.   Because of this THC is medically recommended in conjunction with CBD. Smoking is illegal and not medically recommended as most people think. https://neurologybuzz.com/2018/04/02/medical-marijuana-vlog-series-part-i-mechanisms-medical-benefits-of-non-intoxicating-cannabidiol-and-tetrahydrocannabinol/

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Pitfalls of self-medication

Sometimes patients self-medicate and smoke pure THC from dubious sources to alleviate symptoms, which is illegal and not medically recommended in Florida.  However, the intoxicating effects are not seen when recommended medically using oral forms, cream or patch. At low doses, as is done when recommended medically, THC is non-euphoric. When THC is combined with CBD the side effects of THC are offset. The dangers of patients who self-medicate is that they do not know where the products are coming from and it can be mixed with potentially dangerous substances that can be potentially fatal. In addition, there are highly potent synthetic illegal cannabinoids known as K2 and spice which at high doses can cause cardiotoxicity and fatalities. Self-medicating with THC from an unknown source is highly discouraged as there may be mold involved with the processing. https://neurologybuzz.com/2018/05/31/the-fatal-effects-and-mechanisms-of-synthetic-cannabinoids-including-jwh-compounds-used-recreationally/

Why is a CBD and THC combination important?

In regulated licensed dispensaries, CBD is combined to offset the side effects of THC allowing better tolerance. THC is not recommended by itself because of side effects including paranoia, agitation and hyperactivity.

CBD by itself

With pure CBD, there are certain medical symptoms that are alleviated.

It is legal. There are many companies with CBD products but it is difficult to know how pure these products are, even if you have a small amount of hemp it can be marketed as CBD hence, its ineffectiveness. Some of the most effective CBD products can be found from Colorado and California, anecdotally. Everything else is hit or miss.

In the state of Florida, there are very few medically beneficial CBD products, it’s trial and error. The purer the form such as full spectrum CBD oil the more expensive it will be because processing organic products are costly. A cheap product will likely not be as pure just because of the huge amount of work that goes into extracting the cannabidiol. In addition, some may have flavors, cutting agents and other agents to dilute it but because it’s unregulated.

Ratios

CBD alone has no psychoactivity but medical value. CBD is combined with THC in order to offset its side effects of paranoia, agitation and hyperactivity.

Time of onset and duration

There are different ways of trying it: vaporizer lasts 1 hour and takes about 10 minutes to get into your system. Because the vaporizer is inhaled into the lungs the onset is the fastest because of the rich supply of blood vessels in the lungs. It is advisable to try the vaporizer at home or at night before setting out to see how it affects you. Oral forms last 6 to 7 hours and takes about 1/2 hour to get into your system. Oral form comes in oil concentrate and tincture. Cream and patch last about 12 hours or longer depending on the preparation. Medical marijuana is NOT recommended by physicians to be smoked. Recreational marijuana by smoking is prohibited and unlawful in Florida. This law varies by state. When different parts of the plant are taken together including the terpenes it gives an entourage effect which is more medically valuable than when components are isolated for its use.https://youtu.be/Ir4rwgF2iNc

Are there any edibles in Florida?

As of July 2018, there are no edibles in the state of Florida. It will take an enormous amount of submitting documentation and providing capital before edibles will be implemented in Florida. The dispensaries are working on this.

Registration process: what to expect in Florida

The process includes an evaluation by a qualified licensed physician. https://neurologybuzz.com/2018/07/12/legalities-and-application-process-in-the-state-of-florida/A qualified physician undergoes a 2-hour course and holds a full medical license in the state of Florida. One is evaluated and if patient meets the stringent criteria, they obtain a registry number. The patient undergoes registration which takes between 2-4 weeks. An e-mail arrives before the card then one is instructed to call the office so that recommendations are placed in the system. Oftentimes, if you don’t hear back in 4 weeks it is advisable to give the registry a call. It may be a misentering of an e-mail causing a delay.

Regulated dispensaries in the Florida

In Florida, there are 13 medical marijuana treatment centers and 43 retail dispensaries as of July 2018. In the state of Florida, patients can only obtain the Cannabis products recommended from their treating physicians from these dispensaries. It is illegal to smoke. There are 4 ways of taking it: oral, vaporizer, cream and patch. It is advisable to visit one of the licensed dispensaries in person so that the exact instructions can be given. Physicians recommend orders which are entered into the system. So long as the product is within the number of mg dispensed and the way it is recommended (oral, vaporizer, cream or patch) patients are at the liberty to change the ratio or dosage so long as it is within the orders.

Once you are registered

An e-mail with the marijuana card number comes before the physical card. It is advisable to call the physician office so the orders are placed then physically visit the dispensary of your choice so specific instructions can be taken. Because this is not a pharmacy, doctors do not have immediate access to the dispensary. One should be aware of which product they are taking before their next checkup. This can be easily accessed through the website of the dispensary.

The orders will expire after 70 days after which there is a processing fee of renewal at the office. The certification for medical marijuana expires after 1 year. One must be re-evaluated by their physician before then.

CBD is purely cannabidiol, it is non-psychoactive and legal. THC at low doses is non-intoxicating. Dispensaries combine CBD and THC to offset side effects.  It is federally illegal. It is advisable to be registered under a medical doctor who is qualified to determine if one meets criteria. Medical cannabis products can only be dispensed from a regulated licensed dispensary. Medical marijuana products outside of the jurisdiction of Florida regulates licensed dispensaries cannot be advocated.

Legal implications of THC

In some states, such as Florida, medical use of cannabis is recognized. THC is still considered federally illegal. Recreational use of cannabis is illegal. Smoking THC is illegal. Physicians cannot prescribe it since it is a schedule 1 drug but can recommend it. Schedule 1 drugs are considered illicit and labeled as having no medical use. A statement before the qualifying course on medical cannabis states that the physician can be questioned at any time by the FBI and authorities.

In other states, medical and recreational use is allowed.

In other states, medical and recreational use is completely banned.

The law also varies regarding cultivation of the cannabis sativa plant.

Countries will vary in their marijuana laws.

The laws change very rapidly. Regulations are changed nearly every month with more documentation required from physician offices including consent, doctors’ notes, patient information with indication. As each month goes by another new document is required for submission from the physician office. There is increasing bureaucracy likely signifying resistance at some upper levels against its use related to economic and political reasons. Dispensaries have an equally challenging time. Even worse are small farms applying for licenses huge amounts of capital and documents are required.

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Legal implications of CBD

CBD is legal throughout the US. Countries may vary in their laws since they both come from the cannabis sativa plant.

FDA approved medications and products approved in Europe with CBD and THC

A medication called Epidiolex for seizures with CBD has recently been approved for seizures. Because it comes from a strain from the cannabis sativa plant, cannabis will need to be deregulated from the schedule I category before Epidiolex can be marketed to the public.

Dronabinol has long been approved for nausea and can only prescribed for patients with cancer with chemotherapy induced nausea. It is a synthetic THC and is FDA approved.

In Europe, the medication Sativex which is a combination of CBD:THC has long been used for spasms in multiple sclerosis. This is not available in the US.

In summary

For patients, it is beneficial to have a working understanding of the different strains, different forms that are available in order to obtain the best benefit.  Dispensaries have a huge breadth of products. It is easier to understand as much as possible before facing the overwhelming number of options. Patients must understand all the legal implications in your state as they change rapidly. It is not only a medication it is affected by state and federal laws that change in a blink of an eye which can affect the patient if they are not aware.  One must be mindful that there are different types of practices recommending medical cannabis. The best practices are those that are an already established practice which added medical marijuana to their repertory. Practices that are solely for medical marijuana may be of dubious quality. There are already horror stories of patients never getting a card after several months and phone calls not being advisef on what to do, being examined in a conference hall. As with any new innovative service, there will be legitimate practices and there will be those who meet the minimum requirement of care and service. http://www.tampabay.com/investigations/2018/05/04/floridas-medical-marijuana-program-is-attracting-troubled-doctors-its-like-the-wild-wild-west/

For doctors recommending, one must be well-versed in understanding the potential side effects, drug interactions, the latest scientific research since these are the only guidelines that are guiding us from a scientific level. Pre-clinical studies cannot be ignored nor studies on synthetics to have a better grasp of understanding how it works. One must have a basic understanding in the effects of the phytocannabinoids which is best taken in combination and not in isolation. Patients come with complex medical problems it is always prudent to do due diligence in understanding as much as possible before recommending a product that was never studied for medical purposes in medical school. Patients will ask tough questions, physicians should understand as much as possible and do their due diligence being up to date on legislations as well as the most recent research. The hard questions will come.

One must also follow the legal implications, current regulations which are frequently updated. It is the physician’s responsibility to understand the mechanisms, be current on the literature because this is a pioneering science. Those recommending right now are trailblazing and should still be mindful of the great role you play in understanding what literature is available and to read voraciously.

Last thoughts

While much is still unknown about CBD, THC and mechanisms, there is great anecdotal data from history and clinical anecdotal experience supporting its benefits. While many traditionally trained physicians scoff at the prospect of introducing alternative treatments, one must bear in mind cannabis was not an alternative medication before it was banned in 1830.

While scientists are working overtime in elucidating the mechanisms to combat diseases such as cancer, one must bear in mind that medical cannabis is beneficial when taken in combination with other terpenes found in the plant and the components are not isolated from each other. THC works best in combination with CBD and with other components from the cannabis sativa plant.

When components are isolated from each other and products become synthetic and manufactured much of the benefits are lost and significant side effects result. https://neurologybuzz.com/2018/05/31/the-fatal-effects-and-mechanisms-of-synthetic-cannabinoids-including-jwh-compounds-used-recreationally/

Once it becomes synthetic and components are isolated, the benefits will be substantially altered.

Now is a optimal time to try the benefits of medical cannabis while it is still all organic and being produced on farms and regulated for its use, unsullied by synthetic forms where the risk of side effects are greater.

While much is still to be learned, for a medicine that can easily cover 5 symptoms in one setting, it is an extraordinary time to be recommending and benefiting from medical cannabis while it is still organically natural and pure.

 

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Amyotrophic lateral sclerosis, Epilepsy, Glaucoma, multiple sclerosis, pain, Parkinson's disaese, Peripheral neuropathy, Tumor

Medical marijuana: dispelling myths and fallacies behind cannabidiol and tetrahydrocannabinol

Virginia Thornley, M.D. Neurologist, Epileptologist

Introduction

The endocannabinoid system is found naturally in the brain. It is responsible for the sense of well-being one gets after running a 5-mile course. It does not work through endorphins or adrenaline, as some people may think. It works at the level of the endocannabinoid system. There is a community of CBD producers and consumers and it is in this mysterious world that it is well-known to be used in many medical conditions, still shunned by the majority of the medical community, Congress and even patients in general. The 2 most commonly known are cannabidiol and tetrahydrocannabinol. Cannabidiol has medical properties and has a weak affinity to the CB1 receptor which is predominantly found throughout the central nervous system, which is likely why it is found to work in numerous neurological conditions. Tetrahydrocannabinol (THC) is a well-known cannabinoid most notoriously known for the euphoria of kingpins seen on movies propagated by pop culture. Unfortunately, these connotations overshadow the well-known medicinal benefits. Cannabinoids have been used for centuries even in the B.C. period. It was part of the American pharmacopeia in the 1980’s until it was banned in the 1930’s. Slowly, these products are gaining popularity as a treatment for many medical conditions, primarily neurological because the CB1 receptor is so abundant in the nervous system, due to patients becoming more and more frustrated with the adverse effects and ineffectiveness of conventional treatments. In Europe, a combination of THC and CBD have been used in multiple sclerosis patients since 2010.  Animal studies and cell line culture studies demonstrate many potential mechanisms in which CB1 receptors, CBD and THC may be beneficial at the cellular level in many diseases, mechanisms are still being elucidated. It is most commonly used for chronic pain and epilepsy. As with any medication, it may or not be effective for everybody.

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How it works–the nitty gritty

Cannabidiol has none of the psychoactive properties as THC. One needs 100 times the amount of CBD to have the same intoxication as THC. Therefore, it works well for those who are reluctant to go this route but who have found conventional medications which do not provide effectiveness, they are simply not cutting it. Because very little is know about its titration, medical marijuana can seem like entering into the world of an apothecary, or such as that found in the medieval days when potions are concocted. Physicians who use it in their treat it similar to a medication and the guidelines are similar start low and go slowly.  Tetrahydrocannabinol is more potent and at higher doses works more effectively for pain control and seizures. THC is used at relatively low concentrations in order to effect its medical properties, at higher concentrations one may run into side effects which offsets its medical value. There are different ratios of CBD:THC, different ratios correspond to different symptoms treated.  CBD is required in conjunction with THC in order to offset the potential side effects of THC. Tolerance does not build in the system such as that seen with opioids, although if one is medical marijuana naive, the lowest dose possible is ideal. There are no side effects of respiratory depression such as that seen with other medications for pain such as opioids.Consult with your treating physician.

Current legal state of affairs

Currently, there are many states that recognize the medical value of medical marijuana with medical marijuana laws allowing the opening of licensed dispensaries. However, the same cannot be said for the federal law.  In some states, the carrying of THC on your person can result in fines and imprisonment. Despite marijuana laws enacted, qualified physicians are at risk for being questioned by authorities, its recommendation and use is not for the faint of heart on the part of physicians and patients. Cannabidiol comes from hemp oil and is not considered illegal. However, anyone who even has 1% hemp oil in their product can still label that product as cannabidiol, which may be the reason why some patients are not getting the full medical effects when bought from the flea market or a vitamin store.  Tetrahydrocannabidiol which is more well-known for its recreational use and concomitant psychoactive properties at very high doses is federally illegal in many states. Many states often have registries so patients who require this may obtain an ID and verify they are under the care of a qualified physician. It can take a few months to obtain an ID because many patients are often at the end of their ropes in terms of effectiveness of medications. Many patients wish to come off opioids or do not like the idea of needing higher and higher pain medications for their chronic illnesses. It may serve as a great antidote for the current opioid crisis that is well-documented in the news or overdocumented in the news. Many mothers order products online from other countries to counteract the illegalities of their states in order to help their child who may be using 4 potent anti-epileptic agents and is now like a zombie because of the number of medications. While physicians are leery suggesting anything that is in category 1, its medical value cannot be disputed. There is too much evidence tipping it towards the other side of the scale. As tPA was in its infancy of use and physicians were hesitant using it due to its hemorrhagic adverse effect and is now the standard of care for stroke protocols, medical marijuana will likely find its way back into the pharmacopeia, the amount of medical evidence is far too compelling to ignore.

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In conclusion

In short, when used wisely, cannabidiol is a non-intoxicating effective treatment for many medical conditions especially neurologic, as evidenced by thousands of years of history of its use and current animal models, clinical trials and wider clinical experience in Europe. When cannabidiol is combined with low concentrations of THC, the medical effect is even greater with the entourage effect without the stigmatized psychoactive effects that are usually associated with THC.

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multiple sclerosis

Sativex (tetrahydrocannabinol and cannabidiol) and the European experience in medically refractory spasticity in multiple sclerosis

Virginia Thornley, M.D., Neurologist, Epileptologist
March 12, 2018

Introduction

Sativex has been available in Europe since 2010. It is a combination of tetrahydrocannabinol and cannabidiol at a ratio of 1:1 and has been found to be effective in spasticity resistant to medications in patients with multiple sclerosis. Spasticity is the increased tone seen in the muscles due to abnormalities in the central nervous system such as the white matter lesions seen in multiple sclerosis.

Sativex and medically refractory spasticity in multiple sclerosis

Sativex is a THC:CBD (tetrahydrocannabinol:cannabidiol) preparation taken oromucosally which was approved in European countries for the treatment of medically refractory spasticity in patients with multiple sclerosis. Sativex contains a 1:1 ratio of THC to CBD, where THC interacts with CBD receptors to reduce spasticity while CBD ameliorates the side effects often seen with THC. In one large clinical trial of 1615 patients, 42% showed improvement of spasticity in the first 4 weeks, defined as > or = to 20% reduction in spasticity. The responders were double-blinded and grouped under placebo or THC:CBD, a larger proportion of patients had significant response compared to placebo, > or = to 30% reduction of NRS score for spasticity. 47% had adverse effects including fatigue and dizziness. Reported side effects included psychiatric disturbances, 55 had cognitive (attention problems, cognitive worsening and memory problems) and psychiatric issues (confusion, panic attacks, hallucinations, depression and suicidal ideations). Fatigue, drowsiness, dizziness, gastrointestinal symptoms, mouth discomfort and allergic reactions were other reported side effects. There was no evidence of abuse or addiction in the patients. There were significant side effects deemed unrelated to Sativex including, myocardial infarct, hypertensive crisis (2).

In the original MOVE 2 trial in Italy, in the 322 patients studied, the NRS numerical rating scale decreased by -19.1% from baseline time to 3 months of treatment with Sativex. At visit 3 at 3 months, 24.6% were considered relevant responders to the medication with 30% or more reduction in spasticity. Side effects of >1% included somnolence, dizziness, and fatigue. 41 patients reported side effects 3 were serious side effects of which one was not related (3).

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Sativex and studies in Germany, United Kingdom, Switzerland and Spain

Sativex was first approved in Spain and the United Kingdom in 2010 for use in spasticity related to multiple sclerosis. Data were collected to study continued efficacy and safety profiles.  941 patients (761 from the UK, 178 from Germany and 2 from Switzerland) were studied. Data was collected up until January of 2015.  A patient registry was set up as per guidelines before new medications are approved. Patients from the UK were 22% of the patients registered in the UK using that medication since 2010. Continuation rates were 1 year for 68% of patients. Among those who stopped it, 30% cited lack of effectiveness and 25% described side effects. Some significant side effects include suicidality in 2% and depression in 6%. There was no evidence of abuse, addiction or misuse. The fatigue was within the known safety margins of the drug. The patients used on average 5.9 +/- 4.9 sprays per day

In Spain, 204 patients were evaluated. After 6 months, 143 (70.1%) had benefited from using it for spasticity. After 12 months 64.7% derived beneficial effects. The average dose was 6.6 sprays a day. 41 patients had side effects consisting of psychiatric events, falls, reduced the ability to drive and others. Both study groups in the UK, Germany, Switzerland and in Spain both derived benefits justifying continued used of Sativex. Adverse effects were low, and the mean use of sprays was between 5.9-6.6 which was lower than the clinical trial using 8 sprays (4).

Sativex and timeline when it is found to be ineffective

In one large study in Italy involving 30 multiple sclerosis centers, the discontinuation profile was studied. Patient data from 30 MS centers were collected from a period of January 2014 to January 2015. 39.5% of patients disconnected treatment with Sativex. Spasticity was studied using the EDSS or expanded disability status scale and the patient NRS numerical rating scale 0-10 for spasticity. Information was collected at baseline (T0), 4 weeks (T1), 3 months (T2) and 6 months (T3).

Spasticity was noted in 1615 patients. 1597 (39.5%) discontinued treatment. Of those, 24.8% did not reach 20% effectiveness using the NRS scale. Reasons of discontinuing include lack of effectiveness 23%, side effects 16.3% and lack of compliance 0.8%, lost to follow-up 0.4%, patient choice 0.3% and unknown reasons 2%. Analysis showed that an increase in the NRS scale by 1 point at baseline time corresponded to a lower rate of discontinuation. While an increase in the NRS scale at timeline 2 or at 4 weeks corresponded with worsening spasticity and a higher non-responder rate. They concluded that Sativex is a good option for spasticity and by 4-6 weeks, patients can be reliably identified as responders or non-responders to avoid the cost burden on the healthcare system (1).

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Introduction/Disclaimer

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Reference

  1. Messina, et al, “Sativex in resistant multiple sclerosis spasticity: discontinuation study in a large population of Italian patients (SA.FE. study), Public Library of Science PLoS One, 2017, 12(8) e0180651
  2. Patti, et al, “Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity,” Journal of Neurology, Neurosurgery and Psychiatry, 2016, Sep., 87(9):944-951.
  3. Trojano, et al, “Effectiveness and tolerability of THC/CBD oromucosal spray for multiple sclerosis spasticity in Italy: first data from a large observational study,” European Neurology, 2015, 74:178-185,https://doi.org/10.1159/000441819
  4. Fernandez, et al, “THC:CBD in daily practice: available data from UK, Germany and Spain,”European Neurology, 2016, 75 (supp 1);1-3, https://doi.org/10.1159/000444234
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multiple sclerosis

Multiple sclerosis: stem cell therapy and its role in remyelination

Virginia Thornley, M.D., Neurologist

February 25, 2018

Stem cell research is a fast-growing arm of science. Multiple sclerosis is an autoimmune disease where the central nervous system is attacked as foreign. Clinical symptoms depend on the area involved, primarily in the white matter. Scientific research is being more and more directed towards agents and treatment modalities that differ from today’s immunomodulating agents given the potentially devastating side effects of the more efficacious medications. The heavy hitters tend to be more serious adverse effects.

How stem cell administration works

Umbilical cord mesenchymal stem cells may play a significant role in tissue repair and immunomodulatory processes that are important in multiple sclerosis. Stem cells divide into different types of cells which give rise to different tissues. They hold a wealth of potential in repairing damaged tissue as that found in multiple sclerosis. In one study, the mesenchymal stem cells from the umbilical cord were found with low immunogenicity. They can inhibit the multiplication of killer cells, T lymphocytes, and B lymphocytes and can inhibit the maturation of dendritic cells. Mesenchymal stem cells migrate to the site of injury and proliferate to repair damaged tissue.

Different stem cells that can be used in multiple sclerosis

Other types of stem cells are derived from hematopoeitic, embryonic, neural, spermatogonic, adipose, endometrial, Wharton jelly surrounding the umbilical cord and pluripotent-induced stem cells.

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Stem cell administration in 2 patients and reduction of abnormal MRI abnormalities

In one study, 2 patients were treated with stem cells. Clinical symptoms were reduced in the 1st patient, they were followed 8 years and found without adverse effects. The 2nd patient progressed and the timing of stem cell administration was shortened resulting in the reduction of symptoms. The number of abnormal foci seen in the MRI of the brain was less suggesting remyelination of damaged tissue within the brain. During illness, the body increases the immunogenicity with amplification of inhibitory co-stimulatory signals. With stem cell administration, this process reduces these destructive immune processes. Umbilical cord mesenchymal cells were found to inhibit IL-17c, HLA-DRB1, and IL-2 thereby protecting against an autoimmune response. The mechanism of action by which the stem cells work favors a remyelination repairing the damaged area(1).

Stem cell research in a study of 20 patients and reduction in disability

In another larger study of 20 patients, mesenchymal stem cell neural progenitor was applied. Results showed 70% had improved muscle strength and 50% improved in bladder symptoms. Improved EDSS (Expanded Disability Status Scale) was noted in 40% of patients, there were some minor adverse effects (2).

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Larger clinical randomized case control trials are needed.

References
  1. Meng, et al, “Umbilical cord mesenchymal stem cell transplantation in the treatment of multiple sclerosis,” American Journal of Translational Research, 2018, 10(1): 212-223.
  2. Harris, et al, “Phase I trial of intrathecal mesenchymal stem cell-derived neural progenitors in progressive multiple sclerosis,” EBioMedicine, 2018, Feb., pii.S2352-3964 (18)30051-3 (Epub ahead of print)
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multiple sclerosis

A summary and comparison of the different immunomodulating agents used in multiple sclerosis

Virginia Thornley, M.D., Neurologist

February 17, 2018

Introduction

Research on multiple sclerosis occurs at a dizzying rate. Because there are many newer agents on the market, the treatment options may be confusing for both the patient and even for neurologists wading through a large morass of novel therapeutic options. This seeks to compare and summarize the most current immunomodulating agents in a quick and concise way based on the package inserts, original drug websites and clinical trials performed. It reviews the most common and most striking potential serious side effects, the annual relapse rate reductions and effects on brain MRI lesions (abnormalities in the brain). Some agents were tested against placebo (placebo is an agent with no medicine in it used in comparison studies) others were against older immunomodulatory agents which were previously the gold standard. Currently, there are no head to head clinical trials comparing each immunmodulating agent against each other.  They are listed according to efficacy based on a reduction in annual relapse rate, although some authorities might prefer to compare the effect on MRI lesion burdens. Of note, the most efficacious agents also have some of the most potentially devastating side effects, including cancer and progressive multifocal leukoencephalopathy (PML) which is an irreversible destructive process affecting white matter in the brain occurring in the immunosuppressed state. Consult your neurologist.

 

Older immunomodulating agents

Avonex, Betaseron, Copaxone, Rebif

Mechanism of action: immunomodulation

Efficacy is about 23-25% all very similar

Side effects: flu-like symptoms, transaminitis

Pros: least amount of significant side effect

Cons: least efficacious

 

Newer agents

Aubagio (teriflunomide)

Mechanism of action: reduces B and T cell lymphocyte proliferation, inhibits DHODH required for rapidly dividing cells, exact mechanism is unknown

Efficacy: 30% relative risk reduction in TEMSO trial, 36% ARR (annualized relapse rate)reduction in TOWER trial

57% relapse-free after 108 weeks

Side effects: hepatotoxicity (can cause liver problems), teratogenesis (can affect fetus), bone marrow suppression, hypersensitivity

Pros: efficacious compared to older agents, to date still no reports of PML post-market

Cons: very little

 

Plegridy (peginterferon beta-1a)

Mechanism of action: reduces antigen presentation and proliferation, alters cytokine and matrix metalloproteinase

It is delivered by pegylation, where the medicine is bound to a glycol such that there is reduced renal clearance. Thus, delivery is long spanning 2 weeks.

Efficacy: 36% reduction in ARR

38% reduction in disability progression

Side effects: flu-like symptoms, seizures, suicidal ideations, anaphylaxis, congestive heart failure, autoimmune disorder, abnormal liver enzymes

Pros: efficacious

Cons: very little

 

Ocrevus (ocrelizumab)

Mechanism of action: Ab that target cells with B lymphocytes, Ag CD20 this results in less Ab-dependent cytolysis and complement-mediated lysis

Efficacy:  47% ARR reduction compared with Rebif in RRMS (relapsing-remitting multiple sclerosis)

24% less likely to have a disability in PPMS (primary progressive multiple sclerosis)

Side effects: infusion reactions, hepatitis B reactivation, you cannot receive live vaccine, possible breast cancer

Pros: efficacious

Cons: concern for progressive multifocal leukoencephalopathy found in 1 patient post-marketing, possible breast cancer

 

Tecfidera (dimethyl fumarate)

Mechanism of action: nicotinic receptor agonist, mechanism is unknown

Efficacy:  49% ARR reduction in the DEFINE and CONFIRM clinical trials

38% delay in disability progression compared with placebo

85% reduction in new MRI lesions

Side effects: anaphylaxis, lymphopenia, abnormal liver enzymes, liver injury

Pros: oral, efficacious

Cons: PML found in 1 patient during the clinical trial, few more cases found post-marketing

 

Lemtrada (alemtuzamab)

Mechanism of action: binds to CD52 and depletes T and B cells

Efficacy: 49% less relapses compared with Rebif

65% relapse-free compared to 47% in patients with Rebif

Side effects: joint pain, infections, autoimmune diseases, lymphomas, breast cancer, skin cancer, thyroid cancer and lymphoproliferative cancer, infusion reactions

Pros: efficacious

Cons: Can cause serious autoimmune diseases, lymphomas, breast cancer, skin cancer, thyroid cancer and lymphoproliferative cancer, infusion reactions
Gilenya (fingolimod)

Mechanism of action: immunomodulation, works on the sphingosine 1-receptor modulator

Efficacy: 52% reduction in ARR compared with Avonex

82% reduced disability progression

38% reduction in T2 lesions

60% reduced T1 gad + lesions

Side effects: most common are headache, transaminitis, bradycardia (low heart rate), PML, heart block, PRES or posterior reversible encephalopathy syndrome (reversible damage to the posterior portion of the brain), basal cell carcinoma, teratogenicity

Pros: very efficacious compared to older agents

Cons: some of the worst side effects include PML, PRES, macular edema (swelling of the optic disc)

 

Tysabri (novantrone)

Mechanism of action: blocks alpha-4 integrin, an adhesion molecule on vascular endothelium, reduces activation of autoimmune cells

Efficacy: 67% reduction in ARR compared with placebo

85% reduction in new MRI lesions

Side effects: PML, herpes simplex virus, infections, abnormal liver enzymes, bradycardia, heart block

Pros: efficacious

Cons: risk of PML, bradycardia, heart block

 

In summary, the least efficacious medications are the most benign in terms of side effect profile, while the strongest immunomodulators have the more devastating potential side effects. While clinical trials reflect beneficial conclusions, attention must still be directed towards potential side effects occurring over a prolonged time which may not be reflected in clinical trials which usually involve a timeframe of a few years and do not span over decades. The real test is in the post-marketing groups.  Speak to your neurologist. See package insert for more complete information of side effects.

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