Maine Strong Balance Center in Scarborough, ME is hosting a free event to discuss the evidence for use of aquatic exercise as well as harness suspension systems to improve function in individuals with PD. The event will be held April 6th at 2pm at the Balance Center.
For more information, click: https://www.facebook.com/events/2135389743363771/
An often-quoted statement is that new drug development may take over ten years from the lab to Food and Drug Administration (FDA) approval, and that cost of that research and development may be over a billion dollars. These numbers understandably upset people, especially those suffering from a disease for which treatments are inadequate, or the condition is fatal. During the early days of the AIDS epidemic for example, activists called for the FDA to speed approval of drugs they believed would be life-saving. And, the FDA has developed four ways to speed up approval for drugs to treat serious disease (1):
priority review: FDA attempts to take action on an application within six months
breakthrough therapy: a process to expedite the development of new drugs which may be a significant improvement over available treatment
accelerated approval: a drug for a serious condition, filling an unmet need, and based on a surrogate endpoint, such as improvement in a lab, imaging finding, or physical sign, that is used to predict benefit
fast track: a process to facilitate development and expedite review of drugs for a serious condition, and fill an unmet need
There is also a special consideration for orphan drugs (those drugs intended to treat conditions which affect fewer than 200,000 U.S. citizens) (2) (see the interview with Dr. Moore in this issue on DUOPA). Orphan drug designation allows for incentives to the developer, such as tax credits. Even with these steps, the FDA’s role is that of safety, and the process may still take several years. Consider this 2018 statement from FDA commissioner Scott Gottlieb, M.D. on the mission of the agency (3):
“The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices.”
This brief article is meant to summarize how drugs reach FDA approval (4), and hopefully give a better understanding of why it takes so long to safely bring a drug to the doctor’s office. I hope this writing will serve as a point of entry for other upcoming articles about the drug development pipeline in PD. The article is not meant to disentangle the problem of drug cost, which several authors have tackled (5-7) and is under consideration for a future topic in MPDN.
The FDA lists five steps in the new drug development process. Nested within these steps we find clinical trials. At first, the process may cumbersome to understand, but it can be summarized as follows:
Step 1: Discovery and development, research for a new drug beginning in the laboratory
Most commonly, researchers discover new drugs through a variety of mechanisms: new understanding of a disease process (how something happens in a disease); testing several different compounds to see if they help against a disease (test tube work); observing an unexpected benefit in an existing treatment (for example, a medication for the flu also prevents dyskinesia); or new technologies/ways to target medical products to specific sites within the body or manipulate genetic material. Thousands of compounds may be potential candidates, but most fail, and only a small number may warrant more study.
If a compound is to be tested, information must be learned about it, such as:
Step 2: Preclinical research, drugs undergo laboratory and animal testing to answer basic questions about safety
The two types of preclinical research are: in vitro (outside of living organisms in test tubes or petri dishes, for example), and in vivo (in living organisms such as lab animals or people). These are usually small studies which are meant to find out about proper dosing: how much is enough, and how much is too much. This also helps researchers to decide if the compound should be tested in people.
Step 3: Clinical research, drugs tested on people to make sure they are safe and effective
The FDA makes the following statement (4):
“While preclinical research answers basic questions about a drug’s safety, it is not a substitute for studies of ways the drug will interact with the human body. ‘Clinical research’ refers to studies, or trials, that are done in people…”
The steps through human clinical trials may allow a drug to become FDA approved. Some compounds go through trials but never receive approval.
Clinical trials are often referred to as “translational research,” which brings a drug from the laboratory bench to the human being for testing. Trials at this stage are designed to answer very specific questions related to a drug or device, and follow a protocol that is written prior to starting the study. They must determine the selection criteria (who is included), how many people will be recruited, if there will be a control (placebo) group, how long the study will last, how to give drug, what dose will be given, what questions will be asked in the trial (what data collected), and how that data will be analyzed. Clinical trials proceed from small phase I to large phase III studies.
Phase I trials provide information about how drugs work in the body. These trials typically involve from 20-100 healthy people, or people with the disease being considered for treatment. The study may go on for several months. People are closely monitored to learn how a drug interacts with the human body, how to adjust dosing (usually based on animal data), how much of a drug the body can tolerate, and side effects at the doses given. Per the FDA, about 70% of drugs move to phase II.
Phase II may involve up to several hundred people with the disease or condition, and the study might last years (though the FDA reports it is usually no more than 2 years). These studies aren’t large enough to show whether a drug will be beneficial, and are instead designed to give additional safety data, refine research questions, develop research methods, and design new phase III protocols. Per the FDA, about 33% of drugs move to phase III.
Phase III trials may include thousands of people who have the disease or condition, and the study may last for years. The purpose of a phase III study is to learn how effective a treatment is and to monitor for side effects or adverse reactions (which may be more evident with a longer study and a larger population). These studies may recruit very specific populations of people, and are sometimes known as pivotal studies. Completing a successful phase III trial moves a drug along to what the FDA refers to as step 4 in the overall process.
Step 4: FDA Review, teams “thoroughly examine all of the submitted data related to the drug or device and make a decision to approve or not to approve it”
If FDA approved, it is available for prescription from a doctor. Per the FDA about 25-30% of drugs move to phase IV.
Phase IV studies may include several thousand volunteers with the disease or condition, and are meant to learn even more about safety and effectiveness. These studies are collected after the drug or device has been approved by FDA, and give post-market safety monitoring, also known as step 5 in overall process.
Step 5: “FDA monitors all drug and device safety once products are available for use by the public”
At this point many thousands of patients may be using a drug, and for much longer periods of time than trials were able to cover. This means hidden or rare problems may become more obvious, some of them very serious. A consequence is that many drugs found to be unsafe have been removed from the market over the years. A key issue is that we humans can have very different reactions to medications. What is life-saving for one person may be deadly for another. That is not to say a certain drug which is dangerous for some will always be removed. Instead, it might be the case that it can used by the right person, in the right way. That distinction takes a lot of clarity about the medicines, and about the differences between us. As my second grade teacher used to say, “people are like snowflakes, no two are the same.” It is so true, and it applies to medicine in a deep way. That is why safety is so hard to establish. This applies to “natural” products as well. We are told constantly by advertisers that if something is natural, it is better, or safer. That is not always the case. Natural remedies may be very potent, or they may be very harmful. Just as much scrutiny and care should be taken to make sure any substance given to treat or prevent illness is safe for people. However, in the United States vitamins and supplements are not required to go through the steps above. Sometimes giving these compounds to people results in a bad outcome, and those reports are not rare in the medical literature. For more information on that topic, see the MPDN article “Dietary supplements,” Fall 2016. For more information on drugs in development, stay tuned.
REFERENCES
DUOPA, the dopamine pump, was FDA approved in January 2015 as an orphan drug (drugs or products intended for treatment of rare conditions affecting fewer than 200,000 people in the United States). Though there are probably closer to a million people with Parkinson disease (PD) in the U.S., only a minority would be considered for DUOPA use. DUOPA approval was based on a Phase III, 12-week, double-blind, double-placebo, active control, parallel group, multi-center trial with 71 patients (1). In the trial, DUOPA was compared to oral, immediate-release (IR) carbidopa/levodopa tablets in advanced PD patients. At 12 weeks DUOPA patients had reduced daily OFF time (when medications are not working and symptoms are not controlled) an average of about two hours. At the same time, this group had also improved average ON time (when the medication is working and symptoms are controlled) without troublesome dyskinesia (uncontrolled movement that does not interfere with normal daily activities) by two hours (footnote). Use has been limited in the United States for a variety of reasons. We are happy in this interview to hear about the DUOPA pump from someone who is well-versed in medicine and in PD.
Conner Moore, M. D. is a retired pediatrician who practiced for 40 years in the Saco/Biddeford area until 2008, and worked part-time in 2010. That same year he began to notice the signs of PD. Like his mother, who also had the condition, tremors were never a big part of the disease. Over time, his PD progressed and fortunately he responded to carbidopa/levodopa (Sinemet). As far as I know among Maine movement disorder neurologists, he is the first patient in our state to have the DUOPA pump. Dr. Moore took some time to speak with me by phone and describe his experience with DUOPA at the end of February 2018. This was a casual conversation and he was speaking strictly from his own experience, not offering medical advice on a professional basis, and not representing AbbVie Pharmaceuticals. I appreciate his thoughts and insight.
MPDN: What was your PD like in the years prior to getting the pump?
CM: It started out gradually and on one side like most people. But I was always very active, and I knew that there were studies supporting the role of exercise in Parkinson’s. I took a fairly high dose of carbidopa/levodopa to participate in sports and other activities. It was a trade-off and I knew that might also mean dyskinesias might come earlier. It seemed worth it to me. And, I’ve been involved in the New England Parkinson’s Ride (see article in the summer, 2016 issue) and 4 years ago I was able to complete 30 miles. In 2016 I was only able to do 10 miles and took more rest stops, mostly due to fatigue. Last September, 2017 I wasn’t able to participate because of balance and other factors. Also, I wasn’t using the pump yet.
MPDN: I understand that for the two years leading up to the pump dyskinesias had become an increasing problem, sometimes severe enough to be exhausting, and medication failure was an issue. This led to you taking more frequent doses of carbidopa/levodopa. But, this meant trying to work with diet was also a problem because certain foods might interfere with levodopa absorption. How did you manage that before the pump?
CM: I was taking Sinemet every two hours and was very sensitive to protein with the oral drug. I could eat maybe four grams of protein at a time and I’d have to try to get more in later in the day. All the while, weight loss was a problem.
MPDN: Did carbidopa/levodopa work as long as you took it every two hours?
CM: As is often the case after several years, unpredictable OFF times began to occur more frequently, and sometimes I couldn’t leave the house. Even when I was ON, a troublesome issue was that OFF times would come on suddenly, like somebody slammed a window down.
MPDN: Did you consider other options such as deep brain stimulation (DBS) before the pump?
CM: I saw Dr. Kleinman and discussed options. They don’t like to put the wires of DBS in your brain when you’re older, and I asked about other choices. It didn’t take two minutes to decide about the DUOPA pump.
MPDN: When did you go through this process?
CM: I started using the pump in late September 2017 and participated in the PROVIDE study, which monitored bodily movement for two months prior, and three months after starting the pump.
MPDN: How are the results?
CM: Dyskinesia is now less overall. There is less OFF time. I was getting a lot of blank shots with Sinemet, but the pump works every time. My mood is better, and I can do more around the house. There have been adjustments, but it’s been very good so far. The people at AbbVie have been fantastic and there is a number you can call 24/7. The nurse coordinator is very helpful. After the pump I started to put a little weight back on. It is complicated because some people have actually gone off the pump due to weight loss. Since it was already an issue for me I have watched calories to make sure I’m getting enough. I’m up about 10 pounds. I am exercising and using a Theracycle about 30 minutes daily, also using a stationary bike at the gym.
MPDN: Are there other dietary considerations?
CM: Apropos to your article (B6, friend or foe?, fall 2016), there have been reports of neuropathy with dopamine pumps and I have checked my B vitamins. It is a really fascinating disease. The more I learn about this illness, the less I find that I know about it, and there are new questions. But that is often the case in science and medicine.
MPDN: Too true. The pump requires a PEG J tube, a tube that is placed through the upper abdomen (below the ribs) and enters the small intestine downstream from the stomach. Is it difficult to manage?
CM: Care of the pump, tubing, and the PEG tube is not as complicated as I thought it might be. There is also the opening in your skin for the tube, known as a stoma. The only complication I’ve run into has to do with soup. If I eat a little too much there might be a little leakage, not a big problem.
MPDN: How do you get the medication for the pump?
CM: It comes in 16 hour cassettes air shipped frozen from the Midwest and
FedEx has been right on time, even in a snow storm this winter. It runs on AA batteries but they send those too, they send everything you need. The 16 hour daily cassettes contain the carbo/levodopa in gel form and clip onto the pump. The total unit size is 7.5 x 3.5 inches and weighs a pound. There are vests, hip packs and shoulder slings available to hold the pump. I quickly adapted to my new addition and am generally not aware of its presence.
MPDN: Is it difficult to operate?
CM: There are considerations about operating the pump, a learning curve and some getting used to. It takes some dedication to this project. Most people use the pump during the day and turn it off at night.
MPDN: What is a typical day with the pump?
CM: I wake around 5am and feel I am not yet in an OFF state. I’m able to get up and do a few things around the house for about an hour. Then I start to feel the typical tightening of the face and decrease in left arm swing that let me know I’m wearing off. When I attach and turn on the pump after about 20 minutes there may be a brief period of dyskinesia. After that it levels out. During the day the pump provides a base rate of medication such as 40 mg levodopa every hour. It has given me a sense of freedom. I can go into a theatre now, have dinner, and don’t have to worry about wearing off. If that happens it is much more gradual, a slow process that I can feel coming on, unlike before. If that feeling comes on I can give myself a 50 mg bolus by pushing a little button on the pump and it kicks in within minutes. It has improved my quality of life tremendously.
MPDN: Do you still sometimes have wearing OFF?
CM: There might be wearing OFF with a high protein meal, but I can eat about twice as much protein in one sitting than I could before. The other thing is exercise. Sometimes I need to give myself a bolus if I’m working out too hard. Usually I don’t think about it.
MPDN: Are there any personal limitations with the pump?
CM: I don’t think there is anything I would put in that category. I have only tried one overnight away from home, but have talked with PD pump patients who have traveled with the pump. It requires planning because of refrigeration requirements.
MPDN: How about shutting it down for the day?
CM: At first I was concerned I might have to write down a lot of complicated procedure. There are about 15 steps to turning it off and putting everything away at night, but it all becomes so routine that it’s like brushing your teeth. When you shut it off you flush the tubing with tap water and the nice thing about that is that you are flushing medicine into yourself and get about 30 minutes more levodopa from the tube. Then, it is time to sleep. Not everyone shuts it down at bedtime. Some people run it all night. I don’t think I need that at this time.
MPDN: There is a peer mentor program for people considering the pump. What was your experience?
CM: I used the peer mentor program before getting the pump and met people who had been in the study, and had the pump for about six years. They told me the maintenance was low with the equipment and it had generally lasted that long. I wound up signing on myself for that program. People interested in the pump can call and get one of us on the phone to talk about our experience. It’s a good resource because you are talking to a person with experience.
MPDN: Any last thoughts Dr. Moore?
CM: Just that it has been positive for me, and I hope it helps others to know about this.
Dr. Moore also sent me a comment by email after we talked:
We did not talk about the cost. My Medicare and supplemental insurance pays everything. But I think the President is going to look at entitlement programs to balance the budget. The DUOPA is part of the pump package so it falls under Part B durable equipment and does not go through Part D and the drug insurance process. The government gets a discount, but not much.
Comments by Michael Kleinman, D.O.
The most common indication for the pump is for patients with severe motor fluctuations. If someone is taking medication every 3 hours or less and is still with a significant amount of off time then I would consider them for the DUOPA pump. Traditionally these patients would be first considered for deep brain stimulation surgery but for those patients who may not be good candidates for deep brain stimulation surgery or who are not willing to go through the surgery, then this is a good option. The percent increase in ON time is actually similar to that achieved with surgery.
The company which supplies the medication has a support system in place to help patients get used to administering the medication themselves at home. This has run very smoothly in the experience that we have had here. The medication is started for the first time in the office. At that visit the patient will come in without having taken their medication from the prior night. That visit will be 3-6 hours long. The initial bolus dose and continual infusion dose of the DUOPA infusion will be set based on how much oral medication the patient was taking prior to starting DUOPA. We will then monitor how long it takes for the medication to start working, whether there is evidence of too much medication such as dyskinesia, and whether there is any wearing off. The patient and their caregiver are also educated during that visit on how to operate the pump.
Follow up visits will be more frequent than usual in the beginning to fine tune the dose of medication. If the initial programmed dosing is working well then visits can quickly go back to being every few months. Patients can be given a range of settings to work with at home as well. They can call with a report on how they are doing and be instructed on what change to make to their infusion settings without the need to come in for a visit to have the pump settings changed.
Footnote: In the above mentioned phase III trial of DUOPA, the most common adverse events were listed if occurring in more than 7% of patients, and occurring more frequently with DUOPA than carbidopa/levodopa IR and included complication of device insertion, nausea, constipation, incision site erythema (redness), dyskinesia, depression, post procedural discharge, peripheral edema, hypertension, upper respiratory tract infection, oropharyngeal pain, atelectasis, confusional state, anxiety, dizziness and hiatal hernia.
REFERENCES
Ready or not, it is spring, and time for more articles on MPDN.
This time we include an interview with Maine retired physician Dr. Conner Moore regarding his experience with the DUOPA pump. He very thoughtfully went over his observations on various issues related to choices of treatment with advancing PD, and a few of the ins and outs of using the pump as a patient himself. In that article, Dr. Michael Kleinman of MMP Neurology also gave comment on DUOPA.
As so many of you have raised questions about the topic, we will discuss the drug approval process in the U.S. It is a little complicated, and hopefully that brief article will shed some light and segue into the area of drugs in the development pipeline for Parkinson disease (PD). Regardless of the decision of a certain giant pharmaceutical company to withdraw from PD research, there is a huge amount of work going on worldwide to bring new drugs and therapies to treat PD. The articles included here will be part of an ongoing series on the topic. We will also take an updated look at focused ultrasound (FUS) for PD.
Finally, MPDN is seeing more email subscribers all over the state, and we have now reached 12,000 site visits since we started in April, 2016. We are glad this resource is useful.
Encourage friends and family impacted by Parkinson’s to join us on April 28 to learn about the latest medical research and developments from physicians, receive support and resources, and network and connect with others affected by Parkinson’s. Register today!
8:15 am – 8:30 am
Welcome
8:30 am – 10:00 am
Ketogenic diet in Parkinson’s disease
Dr. Sarah Dodwell, MMC/MMP Neurologist
Yoga Laughter
Denise Macaronas, Certified Laughter Specialist
Focused ultrasound for Parkinson’s disease
Dr. Anand Rughani, MMC/MMP Neurosurgeon
10:00 am – 10:30 am
Break/ Coffee Refill/ Networking
10:30 am – 1:00 pm
Cannabis and Parkinson’s disease
Dr. Roople Unia, EMMC Neurology Specialist
Rock Steady Boxing
Coastal Rehab
Introduction to Mindfulness
Mary Bitterauf, MaineHealth Program Manager
Vitamins and supplements in the treatment of Parkinson’s disease
Dr. Michael Kleinman, MMC/MMP Neurologist
Pipeline drugs for Parkinson’s disease
Dr. William Stamey, Mid Coast Medical Group, Neurologist
Sunday, March 25
2-4 pm
Freeport YMCA
14 Old South Freeport Road
Freeport Maine 04032
The meetings are for people with DBS and their caregivers, as well as people with PD, dystonia, and essential tremor who would like to learn more about DBS.
Future meetings in 2018 will be on:
-Sunday, June 10
-Sunday September 16
-Sunday, November 18
Hosted by the Freeport Parkinson’s Support Group
Parkinson disease conference at Hilton Garden in Freeport, Maine on the morning of Saturday, April 28.
The preliminary theme of the conference is “New Developments- Differentiating promising treatments from pseudoscience” and several brief talks (about 20 minutes each) will cover topics such as supplements, vitamins, marijuana, focused ultrasound, dietary influences, drugs in the development pipeline, mindfulness, and yoga. There will likely be a question/answer session.
Physician speakers will include Dr. Sarah Dodwell and Dr. Michael Kleinman of Maine Medical Partners Neurology, Dr. Anand Rughani of Maine Medical Partners Neurosurgery, Dr. Bill Stamey of Mid Coast Medical Group Neurology, and Dr. Roople Unia of Eastern Maine Medical Center’s Neurology Specialists.
Further details regarding registration, schedule of talks and activities, other speakers, etc will be forthcoming on this website (or via email if you are signed up). It is likely that seating will be limited, so please plan ahead and be prepared to register early if you would like to attend this year.
People with Parkinson disease (PD) have low dopamine stores, and many of the drugs used to treat PD are aimed at either replacing or simulating dopamine. Carbidopa/levodopa (Sinemet) provides levodopa to the brain, which is then converted to dopamine. There is also a class of dopamine simulating drugs, the dopamine agonists (DA). DA are synthetic drugs that are meant to stimulate the basal ganglia (BG) in a way similar to dopamine.
The BG is the part of the brain that uses dopamine to normalize movement and eliminate tremor. The BG is, in a way, the quality control center for movement, is linked to several other parts of the brain, and is involved in various functions. For our purposes here, it regulates learned movements such as typing, playing the piano, handwriting, walking, dancing, or riding a bike. When walking, the BG helps determine how much muscle tone you should use, how far your foot should go when you step, and where it should land. Those functions may fail to some degree when a person has PD (think of shuffling gait, for example). If dopamine is replaced or simulated, the functions may improve. That is the goal in giving these medications.
The reason dopamine replacement helps is because the cells of the BG have structures called dopamine receptors. Dopamine binds to the receptors and the cell is then activated to do something, such as change muscle tone. There are many different cell types and many different effects. DA bind to the same receptors, but there are some differences between dopamine and DA.
One big issue is that after one takes a carbidopa/levodopa pill to replace dopamine, levodopa only spends about 90 minutes in the blood at a reasonable concentration. During that time, it washes through the brain’s blood supply and is absorbed by and stored in the BG. When that happens, the BG can convert levodopa to dopamine, and more or less distribute dopamine appropriately to the cells that need it, as they need it. It is sort of like filling a gas tank. The problem is that the brain’s ability to store dopamine decreases over time in PD, as if the gas tank keeps shrinking. People with PD generally have to take doses of levodopa more frequently over the course of disease because of this decrease.
DA are not stored in the brain, and instead circulate in the blood for several hours after taking a dose.
This means that the entire brain is washed with DA for those several hours, during which time the receptors can be stimulated and symptoms reduced. The effect is weaker than pure dopamine, but often the duration of the drug is longer. This might become a problem, however, because there are other dopamine receptors in the brain that are not involved in movement and yet may be stimulated by the constantly available drug.
A part of the brain that is sometimes affected is the limbic system. The limbic system is involved in craving, lust, emotion, risk-taking, and addiction. Let’s think about risk-taking for a moment. You are with a friend, we’ll say his initials are E.K., and he is a motorcycle stunt artist. He has a really fast Harley Davidson and he likes to pop wheelies and jump over things. It is fun to watch him perform, and he seems fearless. One day E.K. asks if you would like to jump over the fountains at a hotel in Las Vegas with him. For a split second it sounds exciting, and you think, “cool.” Your brain swings into action to deal with this situation.
Let’s talk brain anatomy. There is a part of your brain that analyzes risk. It is called the dorsolateral prefrontal cortex (DLPFC). This is the part of the brain that tries to peer into the future and consider possible outcomes: if X happens, then Y will be the result. It is purely logical (to the extent that you are logical). Its risk assessment says “if you jump the fountains on that motorcycle, you will probably crash: bad idea.” Among other neurotransmitters, the DLPFC is connected to the limbic system with a steady flow of dopamine, and for our purposes, we will focus only on dopamine.
Dopamine generally makes the limbic system feel good, and that seems to be the default.
So, there should be some trickle of dopamine flowing at all times. When you like an idea or the risk is low, dopamine is steady or even increased. When your DLPFC says you should not do something, dopamine flow to the limbic system is decreased. That gives us a negative emotional feeling about the risk and then the logical and emotional parts of the brain can be in agreement. “No thanks E.K., I don’t want to break any bones or die today.” But what if the limbic system is stimulated by DA washing the brain? Does it become harder to follow the instructions of the DLPFC?
For a minority of people, the answer is yes. These people may develop what is called impulse control disorder (ICD).
ICD was defined by the American Psychiatric Association as a group of psychiatric disorders characterized by a failure to resist an impulse, drive or temptation to perform an act that is harmful to the individual or to others (1).
The key word here is “harmful.” Not all behaviors are harmful, and it is important to keep in mind that not everyone agrees on what is considered bad behavior. ICD in PD has been called “hedonistic homeostatic dysregulation” (2) and “dopamine dysregulation syndrome” (3). It should also be noted that ICDs have been reported with all anti-parkinsonian drugs, though it is most often seen with DA.
ICD behaviors can include compulsions for shopping, spending, traveling, eating, sex/libido, reckless driving, and pathological gambling. Patients with ICD may also exhibit obsessive-compulsive disorder (OCD) features such as repetitive behaviors, checking (light switches or locks, for example), religious obsession, sexual obsession, symmetry and ordering, washing, cleaning, and punding. Punding is intense fascination with some action such as writing, repetitive handling, examining, sorting, arranging, craft-making, collecting, hoarding, repairing, or gardening. There is a range of severity from excess interest in hobbies to prolonged stereotyped activity that interferes with normal activities of daily living. If your other interests fail so that you can keep repetitively perform some function, you may be punding.
Patients with ICD often abuse dopaminergic drugs in a way that resembles addiction.
These people tend to take very high doses of drugs and sometimes surpass the upper limits of doses approved by the FDA. Needless to say, they are often not following the advice of a doctor (4), though ICD does sometimes occur at prescribed doses.
ICD is often present when a person with PD has a history of other psychiatric or neurologic disorders such as substance use disorder, antisocial personality disorder, major mood disorder, or anxiety (5-9), though it may occur without these features as well. ICD may be more common in people with young-onset PD. Combining high doses of DA with high dose levodopa is also a risk factor (10).
What can we do about ICDs?
Always follow your doctor’s instructions. Do not change doses on your own. Reducing or stopping the offending medication with your doctor is usually effective. Sometimes a switch to a different DA is helpful. Failing these interventions, caretakers may need to limit access to money or credit cards. Sometimes appointing a financial guardian is needed. One may need to cut off internet access or firewall away gambling sites. PD support groups may be helpful. It is not clear whether other groups such as Gamblers Anonymous are helpful for PD patients. Other medications have been tried, such as opioid antagonists, antipsychotics, selective serotonin reuptake inhibitors, and amantadine.
The person with the ICD is typically quite aware the behavior is unusual and is too embarrassed to admit to it. However, knowing this may be related to medications should give you some idea that it is not unheard of, and can be helped. Telling your physician is a good first step.
REFERENCES
Flyer link: Promotion caregiver fatigue webinar 2018
Tuesday, March 6, 2018
(The webinar also will be recorded for viewing later)
7:00 p.m. (Eastern)
6:00 p.m. (Central)
5:00 p.m. (Mountain)
4:00 p.m. (Pacific)
Webinar will be approximately 30-40 minutes in length.
Register online today by clicking the link below. Or paste the link into your browser.
Registration Link: https://attendee.gotowebinar.com/register/5581056538138946049
In the fall 2016 MPDN article on dietary supplements, I noted that there are studies indicating Parkinson disease (PD) patients may be deficient in vitamins B6, B12, and D. I find that when people learn this they often assume it would be a good idea to pick up some vitamins at the grocery store as a preventive measure. That is not the right move, and is probably a result of years of advertising by industry, to create the false image that vitamins are always safe, and more is better. Vitamins are not benign, and one should not blindly take them.
Instead, just as I advised in the supplement article, if a qualified doctor has found a low level, that doctor can advise you on whether or not you should take a vitamin. If that is the case, stick to the dose directed by your doctor. Don’t improvise, don’t listen to unqualified, however well-meaning people, and don’t believe the majority of what you read on the internet about the topic of vitamins. With vitamins, too little or too much may lead to serious health problems.
Having said that, let’s discuss B12 (cyanocobalamin). Several studies have shown an association with low B12, the total amount of levodopa someone has taken, and peripheral neuropathy (nerve damage in the hands and feet). In other words, the more levodopa someone has taken, the greater the risk might be of that person running low on B12. Low B12 is a common cause of nerve damage. People with PD treated with oral levodopa have a higher prevalence of a mild, chronic sensory neuropathy, though rare cases of severe, subacute neuropathy similar to Guillain-Barré syndrome have been reported (1). The great majority of both types of cases were associated with low B12 levels. The association became more obvious after the dopamine pump was introduced in Europe (2, 3). Continuous infusion of carbidopa/levodopa intestinal gel (LCIG) was associated with a peripheral neuropathy and vitamin B12 and/or B6 deficiency. Cases of LCIG-associated neuropathy often responded to vitamin supplementation without the need for stopping the pump. Investigators advocated for monitoring of vitamin B12 and B6 status before and after patients start LCIG, and vigilance for signs of neuropathy, such as numbness in the feet, tingling, or even burning sensations.
In addition, neuropathy is not the only problem low B12 can cause. Every nerve in the body uses B12, and without it, disease occurs. It might make sense then, to know that B12 deficiency can also cause blindness, memory loss, dementia, and spinal cord damage, which may become permanent. Some patients have told me they know about these issues, and have learned that B12 deficiency can also cause anemia. The logic goes that since they are not anemic, they have nothing to worry about. They are unfortunately wrong. The neurologic damage associated with B12 deficiency is usually established before a person develops anemia. You can’t rely on the presence or absence of anemia to screen for low B12.
Though it is stored in the liver, doctors check B12 with a blood test (with an at least four hour fast prior to drawing blood). It is advisable not to take vitamins before the test, as these will falsely elevate the level, rendering the test useless. Most of the time a level over 300 pg/mL is considered normal. The tricky part is that “normal” levels of this vitamin vary from person to person, and for some a level somewhat under 300 pg/mL may be fine. Fortunately, there is a way to sort this out. Because B12 is necessary for certain enzymes to work, low B12 can cause a buildup in the blood of substances that would have otherwise been broken down, such as methylmalonic acid (MMA) and homocysteine (HC). Think about it like a scale is tipped. When a borderline low B12 level is present and MMA and HC are high, one has a deficiency. In fact, because the B12 blood test may be falsely elevated, MMA is actually a more sensitive test for the state of a person’s B12 storage. In the above-referenced LCIG patients, all of these lab tests verified deficiency.
If B12 is low, it can be replaced by high-dose shots, or sometimes by high-dose tablets, which should again be directed by a doctor. The orally absorbed B12 goes directly into the bloodstream and may be better absorbed than swallowed pills, though some of these are also very effective.
Under normal circumstances, we get B12 from dietary sources, and the minimum daily requirement is about 2.5 mcg, with a recommended daily intake of 6 mcg (six millionths of a gram). A person’s liver will store about 3 mg of B12. A typical American diet contains about 20 mcg of B12 daily, almost all coming from meat or dairy products. Vegan diets can lead to deficiency, and no vegetable product is known to contain a reliable source of biologically active B12. There is some data that the mori, or purple laver of edible seaweed used to wrap sushi might contain sufficient biologically active B12 (4). If a healthy person were to stop ingesting B12 suddenly, deficiency might take up to five years to develop because of those high liver stores.
There are a multitude of other ways one might develop B12 deficiency. These include, but are not limited to: bariatric surgery, taking certain other medications such as proton pump inhibitors or metformin, inhalation of laughing gas (nitrous oxide) and some other inhaled anesthetics, allergic gastritis, and Helicobactor pylori infection. In my neurology group practice B12 deficiency is diagnosed daily.
In the U.S., there is no guideline to check B12 among PD patients. It sounds like a good idea to me, though.
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