From Dr. Trescott’s lecture given to the Physician Partners of America: “Your Genes, Your Pain Drugs and You Or “Why Every Pain Physician Should be Testing Your Genes“
When the patient says, “This doesn’t work,” or, “I’ve been too sensitive,” or, “My mother had a terrible time with medicine X and I’ve had a terrible time with medicine X”, that should really tell you there’s likely to be a genetic problem there. Trescott
We know that many people with fibromyalgia and chronic fatigue syndrome respond very differently to drugs. A drug that works great for one person might have no effect in another person or even make another ill.
Why such variability? I’ve long assumed this meant that many people diagnosed with ME/CFS and FM actually have a different illness, but a recent lecture presented by the Physician Partners of America suggested that’s not necessarily true. It’s possible that underlying genetics or epigenetic changes which affect how our metabolism breaks down substances could play a role.
How you respond to a drug partly comes down to your genes. The human race is very variable genetically. A lot of that variability lies in small genetic variations called gene polymorphisms which can alter how effectively that gene works. These polymorphisms can have no effect or cause the gene to work less or more effectively.
Most people are normal – they have two “good” copies of a gene which allows them to metabolize substances properly. A significant number of people, however, have “good” and “bad” copies of a gene which can inhibit their ability to break down drugs. A smaller number of people (poor metabolizers) have two bad copies of a gene – they hardly break down some drugs at all.
Others with multiple copies of good genes (ultra-metabolizers) can find that even normal amounts of a drug can make them sick as they metabolize the drug into substances that cause harm. Rapid metabolizers of oxycodone, for instance, will produce high levels of oxymorphone, which causes nausea, sedation and other symptoms.
The pain field is a perfect place to look for genetic anomalies in drug metabolism because responses to pain drugs are all over the map. In fact, the process of producing a pain sensation is so complex that some despair of ever producing really effective pain drugs. Part of that complexity lies in the genes that produce the enzymes that break down pain drugs.
The lecturer, Andrea Trescott, MD, a well known pain researcher and doctor, provided a dramatic personal example of the effects a gene polymorphism can have. Her first clue that she might have some hidden genetic vulnerabilities came during a surgical procedure as she was giving birth when she was given Percocet. It had absolutely no effect on her pain.
That process repeated itself during an emergency dental procedure when she was given Percocet, once, twice, three times – and received no relief at all (nor experienced any side effects). She might as well have been eating sugar cubes.
A week later, she went back for another procedure and asked to be given Darvocet which knocked her pain levels out. Subsequently, she found out that genetic polymorphisms in her CYPD26 (or 2D6) gene left her unable to metabolize Percocet. (Ten percent of Caucasians are 2D6 deficient).
Years later, her son, who was also 2D6 deficient, was scheduled to have his wisdom teeth removed. Requesting that hydrocodone, which his genetic status suggested that he metabolized poorly, not be used, didn’t work. Stating that, “of course, he (the surgeon) blew me off”, her son got little relief from the hydrocodone, went back to the surgeon complaining of pain, and was labeled a drug seeker.
Take codeine. Codeine is inert – by itself it has no effects on pain – and has, like many opioid pain relievers, to be metabolized to morphine by the CYP2D6 enzyme to work. Morphine is then metabolized by another enzyme called UGT2B7 to M6G (morphine-6-glucuronide), which has pain-relieving properties. During that metabolic process, though, two other factors are released which can actually increase pain levels.
If you are not metabolizing codeine, you will get little relief from it. If you’re a super metabolizer taking large amounts of codeine, this could actually make your pain worse. Trescott relayed the story of a child with testicular cancer, in terrible pain on 1,000 mg of morphine, but whose pain was under control on just 30 mg. At 1,000 mg, the child’s system was being flooded with pain-enhancing metabolites. At 30 mg, his system was getting morphine and it was working.
Hydrocodone is similar; by itself, it has very little effect, but when metabolized by CYP2D6 to hydromorphone or Dilaudid, it relieves pain. If you find that hydrocodone doesn’t work for you, but Diluadid – which doesn’t get metabolized by CYPD26 – does, you may be genetically designed not to be able to break down many opioid painkillers.
Tramadol – a weak opioid commonly used in FM – is also metabolized by CYP2D6, but in a twist, the same enzyme also controls tramadol’s excretion. If you’re not so hot at metabolizing tramadol, you may end up with poor pain relief plus lots of side effects due to poor excretion.
For the past five years, codeine prescriptions for children have been restricted because of the effects CYPD26 polymorphisms can have on children. The same concerns have lead the FDA to recently release a boxed warning for the use of Tramadol in children. (The problem is probably only relevant for children with a certain genetic makeup, but in them the effects can be severe. Trescott relayed the story of a child with rapid Tramadol metabolism who ended up in a coma in the hospital.)
(Tramadol is metabolized by several enzymes, and because it’s an SNRI, is good for neuropathic pain. The lecturer said it was one of her favorite drugs for pain.)
(Genetic polymorphisms or mutations could even be responsible for the removal of drugs from the market that could have been helpful for many but which harmed people who were unable to metabolize them properly.)
There there’s methadone, which the doctor called her “desert island” drug. At its best, it knocks neuropathic pain out, often causing no side effects at all – a rarity with painkillers. Breaking down methadone is a complicated process, however, and her patients have varying responses to it. When it works, though, it really works.
If your CPYD26 status means you’re not going to get much relief from the “odone’s” (hydrocodone, oxycodone), Tramadol or codeine, there’s still hope. You might do just fine on morphine which is metabolized differently.
The same process occurring in pain drugs applies to antidepressants and other drugs. The CYP2D6 enzyme metabolizes about a quarter of commonly used drugs including many antidepressants. Genetic polymorphisms have so impacted the response to antidepressant drugs that a 2013 Consortium has produced guidelines for antidepressant drug dosing (amytriptyline and nortriptyline), depending on what genetic variations are present in two genes (CYP2D6; CYP2C19).
Its low cost has made Amytriptyline a popular drug, but Trescott called it a “dirty drug” with a lot of potential side effects, in part because of problems some people have metabolizing it.
Drug interactions are another really good way to affect drug metabolism. Trescott relayed the result of a study which found that if you’re taking six pharmaceutical drugs you have a 94% chance of a drug interaction occurring; i.e. one of those drugs is going to impact how at least one other is functioning.
Because Paxil, Prozac and Duloxetine inhibit the CYPD26 enzyme, taking them could make your pain drugs less effective. Taking those drugs together could effectively turn a normal CYP2D6 metabolizer into a poor one. (Celexa and Lexapro, on the other hand, do not inhibit opioid painkiller metabolism).
If you happen to be taking benzodiazepines, tricyclic antidepressants, naloxone or diclofenac — and morphine or its derivatives — watch out because each of these drugs enhances the breakdown of morphine to metabolites which enhance pain levels! (If you’re taking opioids, getting off benzodiazepines might help them work better.)
Note that St. John’s Wort – a herb sometimes used for depression – is a potent CYPD26 inhibitor. If you’re taking St. John’s Wort and your pain, antidepressant or other medications stop working as well, St. John’s Wort may be the reason.
Even something as innocuous as cinnamon can be a problem. Cinnamon can cause oxycodone to metabolize into a substance which doesn’t have strong pain-killing properties.
All over-the-counter stomach medications are not cut from the same cloth. Taking methadone and Rantidine together is fine, but if you take Cimetidine and methadone you could end up in the hospital because Cimetidine inhibits the metabolism of an enzyme called 34A which breaks down methadone.
Because cannabinoids are probably significant inhibitors of the CYP2C19 enzyme, which breaks down Valium, Soma and several antidepressants, people taking cannabanoids may notice changes in the effectiveness of those drugs.
COMT, Fibromyalgia and ME/CFS
Dr. Trescott’s last story involved a gene called COMT whose polymporphisms have been associated with an increased risk for fibromyalgia and chronic fatigue syndrome (ME/CFS). The research on COMT and FM is pretty extensive with the latest study coming just this year.
A 48-year-old male with attention deficit disorder, obstructive sleep apnea, polymyalgia, post-traumatic stress disorder, and chronic low back pain stated he was not responding well to his antidepressants or his ADD medication (methylphenidate) which blocks norepinephrine and epinephrine uptake. An SSRI gave him terrible headaches.
Genetic testing revealed he had reduced COMT activity. Because COMT breaks down serotonin, norepinephrine and epinephrine, his high pain levels were understandable.
Testing also revealed that he had reduced activity of the enzyme that converts methylenetetrahydrofolate to folate, and reduced folate levels, it turns out, are associated with reduced responses to antidepressants and pain medications.
Giving him a folate booster (leucovorin 10 mgs/ morning) and zinc sulfate resulted in a rapid decrease in his pain scores from 9-10 to 2-3 in a week. Plus, his depression and ADD improved.
Hypersensitivity Reactions in ME/CFS
Other scenarios in which genetic testing may be useful include patients who have shown a poor response to medications in the past, those with a family history of drug sensitivity…Argarwal et. Al.
One wonders if the hypersensitivity to drugs and strange drug reactions that some ME/CFS patients experience could be due to a genetic issue or to an epigenetically induced alteration of D26 or other metabolizing genes which occurred when the patient fell ill.
I, for instance, have become extremely sensitive to caffeine. Just a few sips of coffee or tea can send me flying. That didn’t happen prior to ME/CFS. Polymorphisms in two genes (CYP1A2, N-acetyltransferase 2) mainly regulate caffeine metabolism. Could an epigenetic shift have turned me into a super caffeine metabolizer?
Pharmacogenetics is a relatively new field which uses genetic tests to assess a patient’s risk of having an adverse reaction to a drug or their likelihood of responding very well to it. It’s too new for most primary care doctors to be aware of pharmacogenetics, but a primer was recently published that could help guide their use of opioid painkillers. It’s been estimated that over 25% of common drugs have some sort of genetic information which could prove useful.
Genetic testing can provide some answers, but unfortunately is usually not covered by insurance – a mistake, Dr. Trescott thinks, given the 2.2 million adverse drug reactions in the US that cause 100,000 deaths and cost the medical system billions of dollars every year. A variety of genetic panels (CYP2C9, CYP2C19, CYP2D6, and VKOR1, OPRM1, COMT, and ABCB1, as well as dopamine receptors and transporters, serotonin receptors and transporters) are available, however, and more are on their way. Trescott mentioned that Generex [SP] has a program which combines genetic test results with drug intake to determine which drugs are more likely to help.
A group of largely U.S. researchers has created a “Genetic Addiction Risk Score (GARS)”, which uses variations (polymorphisms/mutations) in ten genes to determine one’s risk of having pain problems and/or increased drug or alcohol use. They’ve warned about commercial enterprises which offer bogus gene testing, claiming to be able to predict addiction. See the strange case of Proove Biosciences.
As costs of genetic testing continue to decline, genetic tests at a reasonable price should become more available.
Bottom Line – Doctors Should Listen to Their Patients!
“When they say they’re not getting relief from their medicine, they’re not getting relief from their medicine. Okay?”
The bottom line for Dr. Trescott is that doctors should listen to their patients. If a patient is not responding well to pain or other drugs – if they feel they need more drug to get relief (low metabolizers), they’re not necessarily drug seekers. Or if they’re getting lots of side effects (rapid metabolizers), they are not necessarily complainers or hypochrondriacs.
Pharmacogenetics is being used in cardiovascular disease, and extensively in cancer, but not so much in pain yet. As the research proceeds, though, and the data builds up, it will play a key role in the personalized type of medicine that our medical system is slowly moving to.
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