Pharmacogenetics And Analgesic Drugs

Drug response is a complex trait that is governed by many processes and is multifactorial. The study of the genes that influence drug response is termed pharmacogenetics. The study of the entire complement of genes that influence drug response in an individual is termed pharmacoge-nomics. Though drug discovery progressively incorporates knowledge of the genetic factors that influence their metabolism, genetic tests that can predict an individual's response to a specific drug remain limited. Improvements in both the assessment of gene variations (e.g. microarray methods) and in an understanding of the genes and metabolic pathways that dictate the pharmacokinetics and the pharmacodynamics of drugs are contributing greatly to the development of genetic tests that may predict an individual's response to a drug (e.g. positive, negative). Examples of the pharmacogenetic discoveries in pain and analgesia are listed in Table 4.3.

The potential benefits of pharmacogenomics are manifold. In addition, to being able to identify individuals who will or will not respond adversely to a particular drug, the identification of individuals who may need a different dose will minimize the amount of titration required to obtain the optimal effect and perhaps reduce the number and severity of adverse effects. An additional benefit would be in the area of drug development, where specific pharmacogenetic entry criteria for clinical trials would limit the sample to persons more likely to respond to the test drug. This approach would increase the chance that a given drug would make it to market. In addition, clinical trials would require fewer participants thus reducing cost, decreasing the time to conduct a trial, and reducing the risk to participants. Presumably, this approach would culminate in a reduction in drug costs and allow physicians to prescribe the drug to the patients who would most likely benefit from it.

Table 4.3 Pharmacogenetic candidate genes.

Gene

Name

Trait

Reference

OPRM1

COMT

MC1R

CYP2D6

Mu-opioid receptor

Catechol-O-methyl transferase

Melanocortin-1-receptor

Cytochrome P45G 2D6

Presence of the G allele for rs17181017 is associated with a 41, 42, 43

difference in the standard dose in order to obtain similar effects as those individuals that carry the common allele. Affected analgesics include: afentanil, morphine, M6G, and levomethadone

Presence of the A allele for rs4680 is associated with a difference in the standard dose of morphine in order to obtain similar effects as those individuals that carry the common allele Three polymorphisms associated with a difference in the standard dose of an analgesic in order to obtain similar effects as those individuals that carry the common allele. Affected analgesics include: morphine (polymorphism: 29insA), M6G (polymorphism: rs1805007), and pentazocine (polymorphism: rs1805008; women only) Various polymorphisms and genetic lesions have been associated 46 with altered drug metabolism. Affected analgesics include: tramadol and codeine

Adapted from Lotsch et al.4

Table 4.4 Tools available for the study of the genetics of pain.

Level of inquiry

Approach (methods)

Advantages

Disadvantages

DNA polymorphism (Southern blot) Microarray (multiplex)

DNA is relatively stable and easy to obtain sufficient quantities for analysis

Many DNA variations are of unknown function and may act as surrogates for the causal DNA variation Multiplex analyses can be cost-prohibitive

Multiplex approaches require expensive

analysis

Protein analysis

RNA levels (northern blot)

cDNA re-sequencing

Microarray (multiplex) analysis

Protein levels (western blot)

Peptide sequencing Multiplex protein analysis

Differences in RNA level may be more closely linked to pathophysiology Multiplex (e.g. microarray) approaches may provide information on pathways of gene expression that are altered in trait of interest, providing greater insight into (patho)physiology

Differences in RNA level may be more closely linked to pathophysiology Multiplex (e.g. microarray) approaches may provide information on pathways of gene or protein expression that are altered in trait of interest, providing greater insight into (patho)physiology equipment and specialized training (best pursued via core facilities) RNA is more labile than DNA

Expression analyses require tissue affected by the trait in question Heterogeneous composition of target tissue makes isolation of relevant RNA pool difficult and susceptible to artifact Multiplex analyses can be cost-prohibitive Multiplex approaches require expensive equipment and specialized training (best pursued via core facilities) Protein can be more labile than DNA

Expression analyses require tissue affected by the trait in question Heterogeneous composition of target tissue makes isolation of relevant protein(s) difficult and susceptible to artifact Multiplex analyses are cost-prohibitive Multiplex approaches require expensive equipment and specialized training (best pursued via core facilities)

Notes: Other levels of inquiry include the metabolome, posttranslational modifications, alternative splicing.

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