The variation in response to pharmacological agents between individuals has been recognized for decades.
Unfortunately, the CDC and the other guideline-writing groups are deliberately ignoring this truth. The public is kept ignorant about this criminal negligence of scientific truth (evidence) in the documents created by these groups.
However, the underlying genetic basis that provides a rational explanation for the observation that different individuals can display widely different responses to the same pharmacological agent came to light with the sequencing of the human genome, which allowed the identification of thousands of gene polymorphisms, most often single nucleotide polymorphisms (SNPs)
Polymorphism at the level of drug receptors, transporters, or other proteins involved in drug metabolism or action may have an impact on the effect of a drug, eg, by dampening its efficacy, or by increasing its toxicity.
Genetic polymorphisms for many drug targets and enzymes involved in drug metabolism have been identified, particularly for anti-cancer drugs.
Experts estimate that genetic factors account for 20% to 95% of patient variability in response to individual drugs.
As a result, despite significant advances in pharmacotherapy, challenges related to patient subpopulations experiencing serious to fatal adverse events or not responding to standard therapy remain.
The impact of genetic polymorphism is evident in many clinical areas, including pain management.
Evidence is accumulating that supports the notion that an individual’s specific response to pain or pain treatments may be affected by particular gene polymorphisms.
Cytochrome P450 2D6 (CYP2D6) genotype has been implicated in the response to opioid analgesics that depend on its metabolism for bio-activation.
Variations in the CYP2D6 genotype may determine how well an individual responds to opioid analgesics.
For example, “poor CYP2D6 metabolizers” (PMs) have lower concentrations of active metabolites of
- codeine (morphine),
- tramadol (O-desmethyl tramadol),
- oxycodone (oxymorphone), and
- hydrocodone (hydromorphone),
compared with “extensive metabolizers” of CYP2D6 (EMs), for similar treatment doses.
PMs may therefore fail to achieve pain relief with these opioids compared with EMs.
Mu-opioids receptors are encoded by the OPRM1 gene, and a common missense SNP, rs1799971, has attracted attention as it plays a significant role in determining the response to opiate analgesics.
Summary and Clinical Applicability
Polymorphism of enzymes involved in drug metabolism may underlie inter-individual differences in response to medication and adverse drug reactions.
Although still in its infancy, the field of pharmacogenetics already provides useful clinical information to improve patient care.
- Drug Responses to Pain are Opioid and Pain Modality Specific
- Need for High Opioid Dose Linked to CYP450