Pain Management — PGx Comprehensive | Genetic Testing Services | Kashi Clinical Laboratories

Pain Management

with PGx Comprehensive

Pain Management — PGx Comprehensive | Genetic Testing Services | Kashi Clinical Laboratories

Managing chronic pain is a challenge for healthcare providers because of each patient’s unique tolerance to pain and differing reactions to prescribed medications.

The liver is the principal site of drug metabolism. The enzymes involved in metabolism are present in many tissues but generally are more concentrated in the liver. Drug metabolism rates vary among patients. Some patients metabolize a drug so rapidly that therapeutically effective blood and tissue concentrations are not reached; in others, metabolism may be so slow that usual doses have toxic effects. The drug response differences are associated with differences present in individuals’ genetic makeup. 

Typically, people have two copies of each gene. However, some people have hundreds of copies of the CYP2D6 gene that produces a liver enzyme involved in metabolism of more than one fourth of all prescription drugs. Those with extra gene copies produce too much of the CYP2D6 enzyme and process the drug very fast. As a result, their bodies convert the painkiller drugs like codeine to its active form morphine so quickly that a standard dose codeine leads to morphine toxicity. In contrast, some variants of CYP2D6 that vary by a single difference in their DNA sequence create an enzyme that doesn’t work. People with these variants process codeine slowly, if at all, leading to little, if any, pain relief.

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Examples of genetic markers included in the PGx comprehensive panel:

The genetic variation in response to drugs is referred to as pharmacogenomics (also known as pharmacogenetics). Pharmacogenetics looks at how individuals’ DNA affects the way they respond to drugs. Knowing the patient’s pharmacogenetics in advance can help mitigate adverse drug reactions among genetically-vulnerable individuals and provide information for improved dosage recommendations for therapeutic effect.

Kashi Clinical lab offers pharmacogenetics testing to providers helping them minimize trial and error approach in prescribing medications to treat pain, depression, anxiety and other mental health issues. Although drug metabolism rates are influenced by various factors, it is well known that an individual’s genetic makeup may predispose them to adverse effects and reduced efficacy of medications.

Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the CYP2D6 gene. CYP2D6 is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2D6 is responsible for the metabolism and elimination of approximately 25% of clinically used drugs. CYP2D6 plays a key role in the metabolism of selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (TCA), beta-blockers, opiates, neuroleptics, and antiarrhythmics.

Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme encoded by CYP2C19 gene in humans.  CYP2C19 is a liver enzyme that acts on at least 10% of drugs in current clinical use,[5] most notably the antiplatelet treatment clopidogrel (Plavix), drugs that treat pain associated with ulcers, such as omeprazole, antiseizure drugs such as mephenytoin, the antimalarial proguanil, and the anxiolytic diazepam.  CYP2C19 is an important drug metabolizing enzyme that catalyzes the biotransformation of many other clinically useful drugs including antidepressants, barbiturates, proton pump inhibitors, antimalarial, and antitumor drugs.

Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme encoded by the CYP2C9 gene. CYP2C9 is in particular crucial to the breakdown of non-steroidal anti-inflammatory drugs (NSAIDS) including: diclofenac, naproxen, and ibuprofen. CYP2C9 catalyzes the biotransformation of many other clinically useful drugs including angiotensin II blockers, the alkylating anticancer prodrugs, and sulfonylureas. Of special interest are those drugs with narrow therapeutic index, such as warfarin (Coumadin®, tolbutamide and phenytoin (Dilantin®), where impairment in CYP2C9 metabolic activity might cause difficulties in dose adjustment as well as toxicity.

SLCO1B1 (also known as OAT1B1) is an influx transporter that moves drugs into cells. Variations in SLCO1B1 may affect the blood levels of drugs that are substrates for this transporter. Statins, angiotensin-converting enzyme (ACE) inhibitors and methotrexate are some of the most common classes of medications affected by this transporter. Variations that result in decreased transporter activity may result in increased statin blood levels and increase the risk of adverse effects, such as myalgia and rhabdomyolysis. SLCO1B1-based dosing guidelines are available for statins. Providers should consider genotyping patients who are initiating statin therapy or those who have experienced adverse effects to statins in the past.

Catechol-O-methyltransferase (COMT) is one of several enzymes that degrade catecholamines (neurotransmitters such as dopamine, epinephrine, and norepinephrine), catecholestrogens, and various drugs and substances having a catechol structure. In humans, catechol-O-methyltransferase protein is encoded by the COMT gene. COMT in particular affects morphine dosage requirements and perceptions of pain. A variety of drugs, such as nicotine replacement therapy (NRT), entacapone (Comtan®), opioids, SSRIs, and antipsychotics, may be directly or indirectly impacted by the change in catecholamines inactivation.

Methylene tetrahydrofolate reductase (MTHFR) is an enzyme involved in the methyl cycle and it is encoded by the MTHFR gene. MTHFR helps process folate, a form of vitamin B that plays an important role in DNA synthesis and the regulation of homocysteine levels. The major substrate for MTHRF enzyme is methotrexate, a drug commonly used in chemotherapy and rheumatoid arthritis treatment.

Factor II gene encodes the prothrombin (factor II) protein, one of the clotting factors in blood.

Normally, the prothrombin protein is produced to help the blood clot, and is produced in greater amounts after a blood vessel is damaged. This mutation in the factor II gene results in overproduction of the prothrombin protein. The increased prothrombin protein level leads to a hypercoagulable state, i.e., an increased tendency to form blood clots.

Factor V is a protein of the coagulation system that functions as a cofactor. Deficiency leads to predisposition for hemorrhage, while some mutations (most notably factor V Leiden) predispose for thrombosis.

Factor V and II are blood clotting proteins. Variations in these proteins may increase the risk of dangerous cardiovascular events caused by venous thrombosis. Testing for these genetic variations is indicated for individuals with family history of such events or those at high clinical risk of venous thrombosis, including patients taking medications that are potential contributors.

Mu 1 opioid receptor (OPRM1) is a pharmacodynamic receptor that is known to be responsible for opioid effectiveness. Genetic variants are also implicated in naltrexone (Vivitrol®) efficacy in the treatment of alcoholism and addiction risk to opioids.

SLCO1B1 (also known as OAT1B1) transports drugs into cells. Variations in SLCO1B1 may affect the blood levels of drugs that are substrates for this transporter. Statins are one of the most common classes of medications affected by this transporter. Variations that result in decreased transporter activity may result in increased statin blood levels leading to adverse effects, such as myalgia and rhabdomyolysis.

The human gene VKORC1 encodes for the enzyme Vitamin K epOxide Reductase Complex (VKORC) subunit 1. In humans, mutations in this gene can be associated with deficiencies in vitamin-K-dependent clotting factors. VKORC1 is the site of action of warfarin and genetic variation in VKORC1 increase or decrease the amount of warfarin needed to inhibit the formation of the clotting factors. For example, when warfarin dose exceeds the required amount, the risk of bleeding is increased.

 Apolipoprotein E (APOE) is a fat-binding protein that plays a role in lipid transport in the blood and the brain. The APOE4 variant increases the risk for development of late-onset Alzheimer’s disease two- to threefold for individuals with one copy of the APOE4 variant. This risk increases by 10- to 15-fold for individuals who carry two copies of the variant (E4/E4 genotype). The presence of APOE4 may also lead to earlier development of symptoms in patients with late-onset Alzheimer’s disease. Despite the strong association,  the presence of APOE4 is neither necessary nor sufficient for the development of Alzheimer’s disease. More than 35% of patients with late-onset Alzheimer’s disease do not have an APOE4 allele.

Example Table of CYP Metabolizers by Phenotype

Results from Kashi Health’s Pain Management Panel classify patients by how effectively a patient is likely to metabolize a medication. This classification is based on how many copies of functional or variant alleles inherited. In general, the genetic variability of CYP genes can be grouped into four phenotypes: ultra-rapid metabolizers (UM), normal (extensive) metabolizers (EM), intermediate metabolizers (IM) and poor metabolizers (PM).

Type of Metabolizer
Genetic Variability Effects

Ultra-rapid metabolizer (UM)

Increased enzymatic activity due to duplications or multiplications of the functional allele

Extensive metabolizer (EM)

Normal enzymatic activity due to the presence of at least one functional allele

Intermediate metabolizer (IM)

Moderately-decreased enzymatic activity with either two decreased activity alleles or one decreased activity allele and one null allele

Poor metabolizer (PM)

Lack of enzyme activity as a result of two null (non-functional) alleles

Limitations of pharmacogenomics

Interactions with environmental elements and other medications need to be taken into consideration with the genetic makeup of the patient when determining efficacy of a drug. Rare genetic differences may not be detected because the panel screens for the most common and well documented gene variants.

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