The Proove genetic test for fibromyalgia – is the first genetic test that I know of for FM. It’s not a diagnostic test – it’s focused on guiding treatment options. It identifies ten genes that can affect drug metabolism and one gene that affects pain sensitivity, anxiety and other symptoms.
Since our genes may affect up to 50% our sensitivity to pain and because fibromyalgia appears to be at least partly heritable, a genetic test for FM could be very helpful.
Many drugs require the body to break them down into their active components to work. Genetic polymorphisms which reduce or even completely inhibit an enzyme from metabolizing a drug can cause that drug not to work or to have increased side effects. Polymorphisms, on the other hand, that cause drugs to be metabolized too quickly can cause similar problems.
The new Proove FM test seeks to help doctors determine which drugs might or might be helpful for FM patients
We carry two copies (alleles) of each gene in our body, one from each parent. A 2000 literature review found at least one gene polymorphism (single nucleotide polymorphism or SNP or variant was able to affect the metabolism of more than half the drugs available.
These gene variants or SNP’s – passed down through evolutionary times – can vary racially. Thirty percent of Asians and African Americans carry SNP’s in the CYP2D6 gene that can result in the slow metabolism of many antidepressant or opioid drugs. Ten percent of Southern Europeans, on the hand, carry a SNP that results if very rapid metabolism of those drugs.
Please note that genetic findings almost always denote tendencies and are not determinative. Epigenetic modifications can turn off or on genes and environmental influences may alter the effects of genes; i.e. you can have a SNP that affects opioid metabolism and still do OK on them. These findings are based on studies of different size and effectiveness as well, and only one two SNP’s on the panel have been tested in fibromyalgia. This is clearly an evolving field.
It does provide, though, one angle that can help doctors and patients more quickly find better treatments. Dr. Ginerva Liptan M.D. reported in a recent blog, that she believes these genetic analyses give doctors and patients a “head start”. She talked about one FM patient whose genetic analysis uncovered why he responded so poorly to antidepressants.
This test is not cheap ($799) and insurance companies will not pay for it, but it does present a way some people with FM might be able to get a better handle on what drugs might work for them.
In this blog I took a look at the SNP’s found in the Proove fibromyalgia panel by doing PubMed searches using the terms “fibromyalgia + the SNP” and “pain + the SNP”. Several overviews played a large role in the blog and some studies were surely missed as well; i.e. it’s not a comprehensive overview.
The Genes
OCT1
Morphine – OCT1 plays a major role in the uptake of morphine by liver cells. Some OCT1 polymorphisms can greatly inhibit morphine uptake by these cells. OCT1 polymorphisms that are more frequent in Caucasian children may reduce the clearance of morphine from their systems resulting in more adverse side effects.
Triptans Drugs – Migraine is not uncommon in fibromyalgia. Polymorphisms in OCT1 have not been associated with fibromyalgia but polymorphisms in this gene can reduce or even abolish the ability of cells to take up sumitriptan and probably other migraine drugs.
CYP3A4 – The Elephant in the Room
It has been estimated that CYP3A4 enzyme metabolizes about half of all drugs found. That’s a bit unfortunate because many commonly used drugs actually inhibit CYP3A4 functioning. Other drugs can activate the enzyme resulting in too much enzyme activity and a reduction of effectiveness.
Opioid Drugs and Clonzepam – Different polymorphisms can reduce CYP3A4 metabolism of opioids such as buprenorphine, fentanyl, hydrocodone, meperidine, methadone) and clonazepam as well as many other drugs.
- Check out a list of drugs that inhibit and induce CYP3A4 activity here.
UGT – Uridine diphosphate glucuronosyltransferase
Morphine – the UGT2B7 enzyme metabolizes morphine into one compound (morphine-6-gluceronide (M6G)) which reduces pain, and one compound (morphine-3-gluceronide (M3G), which actually causes more pain (!). People with UGT2B7 gene variants that metabolize more of morphine into the M3G compound may find that morphine is either ineffective or increases their pain levels.
Drugs That Inhibit UGT2B7 – As noted above, another aspect of drug dosing concerns drugs which inhibit the activity the enzymes that break down other drugs. Because tamoxifen, diclofenac, naloxone, carbamazepine, TCAs, and benzodiapines are all inhibit activity of the UGT2B7 gene using these rugs could interfere with the effectiveness of opioids.
CYP1A2
Cymbalta – If you haven’t responded to Cymbalta (duloxetine) it could be because of the variant of CYP1A2 gene that you have.
Triptans – Similarly, if you have migraines you might want to note that one variant of CYP1A2 has been associated with triptan overuse and abuse.
CYP2D6
CYP2D6 -Is a highly variable gene that has significant effects on opioid metabolism. So many variants of this gene (over 100) have been found that people have divided into the following categories:
- Extensive metabolizer (EM) – EM’s have two normal or “wild type” alleles and is considered “normal.”
- Intermediate metabolizer’s (IM’s) – have one normal and one allele with reduced activity or 2 alleles with partially reduced activity.
- Poor metabolizer’s (PM’s) – have two alleles that result in very limited or complete loss of enzyme activity
- Ultra-rapid metabolizer’s (UM’s) – have multiple alleles that result in the very rapid breakdown of a particular drug
Morphine – One study showed that 70% of patients in severe pain were poor metabolizers for the CYP2D6 gene. On a better notne, other studies indicate ultra-rapid metabolizers need less morphine to reduce their pain than the other types of metabolizers.
Codeine – is metabolized by CYP2D6 into its active form, morphine. Poor metabolizers of codeine may get absolutely no relief at all from codeine.
Tramadol – Tramadol, a commonly used drug in FM, is metabolized into eleven different compounds, some of which have varying pain relief properties. Poor metabolizers of tramadol generally require more Tramadol than normal metabolizers.
If you’re a rapid CYP2D6 metabolizer, though, your Tramadol may be metabolized to a metabolite that is at least six times as potent as Tramadol – and therefore you may need less of it.
Hydrocodone – The CYP2D6 enzyme metabolizes hydrocodone into hydromorphone which is more effective at binding to opioid receptors. If you have a CYP2D6 gene variant that reduces metabolism you might not find hydrocodone effective or might require higher doses of it and/or suffer from more side effects.
Drugs known to inhibit the activity of this gene include fluoxetine, methadone, celecoxib, buproprion and others
HTR2A
Depression is pretty common in fibromyalgia. If you experience it, it may at least partially due to your genes. The serotonergic (5HT) system helps regulate pain, depression and physical functioning. Variants of the HTR2A gene have been associated with increased severity in FM and other pain disease. People with these variants tend to use more pain reducing drugs.
5-HT2A/2C antagonists – On the bright side, people with one particular 5HT2A SNP or gene variant may experience less pain and/or depression or increase physical functioning when taking 5-HT2A/2C antagonists. Others without that variant may not. People with some versions of these genes may not respond to the pain or depression reducing properties of antidepressants.
CYP3A5
Opioids – CYP3A5 is one enzyme whose expression depends, in part, upon race. Asians with several common CYP3A5 or 5 mutations may need fewer opioids to reduce their pain.
CYP2C8 and CYP2C9: the NSAIDS Genes
NSAIDS – People with CYP2C9 polymorphisms may experience more bleeding when taking over the counter pain relievers such as ibuprofen and diclofenac. These polymorphisms inhibit the metabolism of these NSAIDS allowing them to impact the stomach more. People with these polymorphisms might want to try drugs that operate using different metabolic pathways.
COMT
The COMT enzyme plains an important role in pain sensitivity. Variations in the genes that encode this enzyme are believed responsible for about 10% of the pain one experiences. COMT metabolizes catecholamines (dopamine, epinephrine, and norepinephrine) and plays an important role in dopaminergic and adrenergic/noradrenergic/serotonin neurotransmission.
The common COMT variant – the Val158Met form – plays an important role in pain. People with the homozygous version of this gene have increased pain sensitivity. On the other hand, they may need lower levels of opioid drugs to deal with their pain.
People with reduced COMT activity are more prone to pain and pain catastrophizing.
A metanalysis found that people with fibromyalgia had an increased incidence of several COMT gene variants and that people with FM with one variant experienced more pain. Another suggested that that variant affected the activity of sympathetic nervous and humoral immune systems.
Conclusions
The Proove genetic panel is expensive but may be able to help physicians and patients find better drug options and stay away from drugs that may be harmful. Much clearly, however, remains to be learned regarding fibromyalgia, genes and treatment options. (Genetic information on the effectiveness of Lyrica, for example, would be great.) Future research will hopefully produce many more genetic insights into pain and FM.
The Great Chronic Fatigue Syndrome Gene Project – Got Chronic Fatigue Syndrome and want to help researchers better understand the genetic contributions to it? Enroll in The Great Chronic Fatigue Syndrome Gene Project
Health Rising is not affiliated with Proove in any manner
Do you think that this panel would help uncover drugs that might be tolerated, as well? I have avoided trying several drugs for fibromyalgia because I’m so extremely drug sensitive, and I’ve had so many side effects from the small doses of those I’ve tried, but pain is increasingly a problem. I also have CFS, and I’m wondering whether the genes involved in CFS would interact in such a way with the genes studied in this test that the results would not be helpful.
Doesn’t take into consideration of our drug sensitivities.
These are all on 23andme for about 1/4 the price. Genetic Genie’s detox profile will give you info on most of them and the rest you can look up in the raw data.
Honestly, does anyone need to spend $799 for this? Ultimately it’s going to come down to trial and error anyway because these genes aren’t really predictive of much of anything.
I have a ton of CYP mutations for example, but I handle most all forms of pain meds just fine.
Good point….What you will get I suppose is Proove’s information on the SNP’s – they undoubtedly have more information than I provided – and ease of use but as you point out you can get information on these and a lot more by doing a bit of digging for a lot cheaper.
I was surprised at the cost as well. If 23andMe can provide the raw data for entire genome for $200 why does it cost $800 for Proove to provide information and 11 genes?
Thank you. You just saved me $800
🙂
Just a heads up!! I’ve had genetic testing several years ago from 2 different companies: Genelex and Gensight due to problems with pain meds and anti-depressents. It was very frustrating when I ended up with two very different results. The National Institute of Health has published an illuminating blind trial study of genetic testing results with samples from a defined group of people sent to 5 different genetic testing companies. The problem is a lack of standardization in the genetic testing procedure which can result in high variations. Genetic testing can be done in varying “depths”; not the right word, but the more “detailed” test did concur with my lifetime of documented medication issues. So if your test results do not concur w/ your life experience, it doesn’t necessarily mean that the problem is NOT in the testing methodology – they are all different.
I think it’s odd that the panel doesn’t include the OPRM1 gene analysis. According to ARUP (a laboratory), OPRM1 gene analysis can help to:
• Predict response to opioid agents
• Pretherapeutic identification of individuals who may
oRequire higher or lower doses of opioid drugs to achieve adequate pain control
oHave a better response to naltrexone for the treatment of alcohol and/or opioid dependency
I have the mutation – according to my pain doc (Dr Tennant), I can expect to have half the normal response to opioids as someone without the mutation.
In my work as an anesthesiologist I see a huge range of responsively to opioids. Many health practitioners are quick to label patients are “users” that are lying about their use, simply because they require higher than normal doses of opioids for pain relief. Genetics tells us this is nonsense.
Thank you for the interesting review.
There were a couple genes I came across I was surprised they didn’t include. What a shame that some people who are asking for high levels of opioid pain killers may just not be metabolizing them well.
Where did you folks find 23andme providing those gene analyses, could you post link? They didn’t have any of them in their ancestry plus health or whatever they call it when I looked. Is there a higher level I missed?
You can download your genetic profile. It’s in one of those tabs at the top of your home page at 23andMe. You can plug those into various sites such as Genetic Genie. I gave them to a GYN I see who is using the info to indentify SNPs and try to figure out what to do to address them. She’s still learning, as everyone is.
So annoyed that you’re promoting this DNA TEST.
I took this with CFS/ME/POTS/FM with a migraine. There answers are skewed by labeling others as an exaggerator because of the degree of difficulty on daily routine things. Please don’t take this test until they acknowledge how severe and real ME/CFS/OI ARE. CONCERNS ME THAT The Results do not explain tolerance and sensitivies. Like I can’t take asprin or NSAIDs. this test is very flawed. For profit company that won’t respond to my concerns.
Honestly, I’m really trying to inform and learn about this test more than anything else.
I agree with you, Cort, you are providing valuable info, please continue, we can decide how to use it! As an aside, whether to try to get an insurer to pay for this test kind of brings up the same issue as the fibro test; depending on results they may try to control your treatment.
I’m with you but be warned. This could end up as the new pace trail. Very flawed. Until they can figure out what drugs we can tolerate or have major sensitiveties too I feel it’s dangerous and damaging to our care. Subjective Questions on our pain level and degree of difficulty. Huge problem. Understanding metabolism or bioavailability of our DNA and drugs is different. They need to be more aware of ME/CFS/FM/OI. And more improtalty our cognitive impairments. Please be warned.
I got pos result on CYP2C19, can you explain what that can do? I have had bleading ulcer when I used a lot of NSAIDS together with omeoprazole. What kind of medication dos it affect? I havent had it explaind from the doc, just got the result in the mail.
I was so thrilled to see the title of this article, as I have recently had this test done. I see a pain management doctor for treatment of chronic pain as a result of fibromyalgia, CFS, and arthritis in my back and hips, chronic migraines and Hypothyroidism/hashimoto.
My pain management doctor just “made” me or should I say I was “strongly encouraged” to participate in what was presented to me as a research study to determine whether or not I “was” or “would become dependent” on pain medication based on my generic make up.
Of course this test was presented to me as just another routine test to follow the standard routine urine drug test until I started asking questions about it, then the staff member that I later found out actually worked for Proove, (I did not find this out until my doctor’s nurse overheard me questioning whether or not I had to submit to the test and basically made me feel like I didn’t have a choice, and I had taken the test, and gotten the results.) I immediately had some concerns about such a test, which I had no prior knowledge of, no information on the reliability of the results, how any possible results may affect my relationship with my pain management doctor which I have been seeing for years with no issues, etc.
After questioning the “research study, the staff member from Proove went on to explain to me that this test would also provide my doctor with information that would help them determine how to better treat me, help me prove if necessary that a particular medication is not working, how sensitive I am to pain tolerance, and what medications worked for me and which ones didn’t.
Still feeling slightly pressured at this point, I agreed to take the test. Later, through my own investigation, I learned that this test was not given to “all patients that are prescribed pain medication at this office which really did not sit well with me. I first confronted the nurse with this by asking her if all patients were asked or encouraged to take this test like I was; after she stumbled around trying to figure out how to not answer the question, which I already knew the answer to, I then addressed this same issue with my doctor. Keep in mind, this test at all times has been presented to me as a “research study”. I flat out told my doctor that I knew first hand that there was other patients being prescribed pain medication that were not asked to participate in this test/study, and I wanted to know if I was being singled out and why? She then told me that the criteria was based on what type of medical insurance the patient had!!! My doctors office did attempt to bill the costs of this “research study” to Medicare for an outrageous amount, it was well over $799.00, but thankfully Medicare denied the charges and stated it was an unallowable charge and further stated my doctor’s office was not allowed to charge me any part of these charges.
The kicker to this entire process is that since receiving my results, my doctors office has not done anything to change my medications based on the results of the test. At my second month appointment after receiving the results, I am the one that pointed out to my doctor that the test results revealed that the anti-depressant I have been being prescribed for a lengthy time is metabolized by my body too quickly, therefore I would not receive any relief from the medication. I asked if I should continue taking this medicine or if there was something better that I could be switched to……
I don’t have enough information at this point to say whether or not I am thankful I took the test or if I think I may regret it at some point in the future for reasons I am not aware of yet…
At this point, my biggest issue is that I honestly don’t know how to really interpret the results in a way to make what I would consider any changes to better my health.
I also took a copy of the results to both my primary care physician and my pharmacist, neither of which seemed interested in examining the results, as if they didn’t seem to think the results would be helpful in my care.
At this point, I would definitely not pay for this type of test, I haven’t found anyone yet that seems all that concerned about the results, including the doctor that “strongly encouraged” me to take it in the first place.
Cort, if you are knowledgeable about these types of things and could help me to interpret the results, or if you are merely curious about what the results of these tests reveal and/or think they would help you in further researching this subject, I would be happy to share my results with you.
Really interesting experience – thanks for sharing that. I think this shows how new this stuff is and how doctors are learning to fit it or not fit into their practices. Dr. Liptan really welcomed the test in her blog but other doctors are apparently not applying it very well.
She welcomed the test but it’s not clear if she took it and I asked why on her blog.
Cort, after going to Dr. Lipton’s blog, I realized the Proove test that I had done was not the one for Fibromyalgia.
The one I had done was much more in-depth and included testing for Opioid Risk, Drug Metabolism, Pain Perception, NSAID Risk, Opioid Response, Non Opoid Response, and Mat Response.
With these types of tests still being so new, I guess I still have my concerns about the accuracy of the results. CATHERINE’S comment above confirmed my biggest concerns.
Then you have to worry about how these types of results, accurate or not, might be interpreted by someone who may/may not fully understand them.
For example, testing someone’s predicted risk for Opiod Dependency and Abuse based solely on genetics.
I do see where this would prove to be helpful, bu first I would need validation of the results.
Also, with regard to VLYNX’S comment above, my test also did not include analysis for the OPRM1 gene. It did give a detailed list of medications, and list whether or not I would be a good or poor responder, and at what dose and frequency.
I am looking forward to seeing more research about this and hope that this testing proves to be helpful in the treatment of chronic illnesses. I do suspect this is just the beginning of this type of testing.
I mentioned recently that I had done the Ancestry DNA-Canada test and only got back heritage and no medical info.
Due to lack of standardization, medical ethics and the fact the “patient” doesn’t necessarily have a doctor to explain the results can lead to a slew of problems, if you think about it.
Therefore some companies are not doing the medical genetic info.
I am repeating the process through 23andMe as I’ll be uploading the info for Dr. Klimas’s study
Catherine, Please post where one can find info on The National Institute of Health blind trial study of genetic testing results you refer to. Thank you.
I underwent genetic testing with Genelex because I had problems with antidepressants and pain meds that were being thrown at me and I kept having elevated liver enzymes with no known cause. 5 genes were tested and 4 were abnormal. With guidance from a physician, I can plug in medications to their program and predict if there might be a complication. Of course, now I don’t take pain meds anymore and I’ve found 20 mg of Celexa to be just right.