The efficacy and tolerability of painkillers can be influenced by the patient's genetic disposition.
In this section:
- Opiod therapy
- Therapy with nonsteroidal anti-inflammatory drugs
- Butyrylcholinesterase (BCHE) deficiency
Opioid Therapy
When treated with certain opioids such as codeine, tramadol, oxycodone, or tilidine, there is a risk of genetically determined therapy resistance or intoxication. These drugs are so-called prodrugs, which only become effective after being converted into their active metabolites. For codeine, tramadol, and oxycodone, this conversion is primarily mediated by the CYP2D6 enzyme; for tilidine, activation occurs, among other pathways, via CYP2C19. For both enzymes, there are known variants resulting in either slow or ultra-rapid metabolizer types, which can impact the efficacy and tolerability of these medications.
Impaired or absent enzyme activity can lead to therapy resistance with these drugs, as insufficient amounts of the active metabolite are produced. If suspected, testing for the "slow metabolizer type" of the respective enzyme can be requested.
On the other hand, increased activity of the involved enzyme may quickly produce high concentrations of the active metabolite morphine, which can lead to intoxication. In such cases, testing for the "ultra-rapid metabolizer type" may help clarify the situation.
Therapy with nonsteroidal anti-inflammatory drugs (NSAIDs)
Medications such as ibuprofen, celecoxib, piroxicam, and other nonsteroidal anti-inflammatory drugs are metabolized, among other pathways, via CYP2C9. Patients with reduced enzyme activity may thus exhibit elevated levels of these substances, which can lead to adverse reactions. If there is a relevant suspicion, testing for the slow metabolizer type of CYP2C9 can be performed. However, ineffectiveness of NSAIDs cannot be clarified on a molecular genetic level, as no ultra-rapid metabolizer type is currently known for this enzyme.
References
Summary of product characteristics of the respective active substance / annotation of the FDA label of the respective active substance
DPWG Guideline for tramadol and CYP2D6 / DPWG Guideline for oxycodone and CYP2D6 / CPIC® Guideline for codeine and CYP2D6 / Swenn et al., Clin Pharmacol Ther. 2011; 89(5):662-73. / Grün et al., Br J Clin Pharmacol. 2012;74(5):854-63.
Butyrylcholinesterase (BCHE) deficiency
Postoperative apnea is a serious complication associated with the administration of certain muscle relaxants (e.g., suxamethonium, mivacurium), which are broken down by the enzyme pseudocholinesterase (BCHE). Other substrates of BCHE include procaine, tetracaine, cocaine, and heroin. Various pathogenic variants in the BCHE gene can lead to reduced enzyme activity and consequently to delayed metabolism.
BCHE deficiency is inherited in an autosomal recessive manner, meaning that both alleles must be affected for clinical symptoms to manifest. If the deficiency goes undetected, acutely life-threatening situations may arise during or after anesthesia. The A variant (atypical variant, p.(Asp70Gly)) is associated with a reduction in enzyme activity to about 30% of the normal value and with severe anesthesia-related complications. In contrast, the K variant p.(Ala539Thr) is associated with a moderate reduction in enzyme activity to approximately 70% of the normal value, which typically does not result in a prolonged succinylcholine response. However, it cannot be ruled out that the K variant may become clinically relevant in combination with other factors (e.g., pregnancy, anticholinesterase medication, pre-existing conditions). The allele frequency of the A variant is estimated at approximately 2% (homozygous frequency 1:3,500), and that of the K variant at about 12% (homozygous frequency 1:100) in the Caucasian population. Analysis of the BCHE gene can be requested as a stepwise diagnostic approach, with step I detecting the K and A variants. Step II involves a mutation search across the entire BCHE gene to rule out rare variants. Prior to genetic testing, biochemical measurement of pseudocholinesterase activity can provide insights into BCHE deficiency.
References
Zhang et al. 2018 Medicine (Baltimore). 97(52):e13714 / Gätke et al. 2007, Pharmacogenet Genomics 17:995 / Levano et al. 2005, Anesthesiology 102:531 / Bartels et al. 1992, Am J Hum Genet 5:1086 / McGuire et al. 1989, Proc Natl Acad Sci USA 86:953
