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.
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.
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.
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 -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
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.
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.
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.
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
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