Genetic Polymorphism as a Possible Cause of Severe Postoperative Pain.
In the Western world, up to 80% of patients still experience postoperative pain, with a majority even complaining of moderate to extreme pain. Adequate postoperative pain management may facilitate early mobilization, improve postoperative outcome, and reduce the length of hospital stay.1, 2 In (chronic) pain therapy, the use of pharmacogenetics (PGx) has emerged as an encouraging tool by identifying genetic biomarkers that can predict individual analgesic response and possible side effects, opening doors to precision medicine. We report a case of a 22-year-old red-haired White man with a history of Russell Silver syndrome, cannabis use, and a major depression treated with venlafaxine. He underwent a unilateral orchidectomy in January 2020 because of a nonseminomatous germ cell tumor (pT2N2S1). Contrast computed tomography scans were performed in search of metastases, and a retroperitoneal para-aortic lymph node metastasis was identified. He had undergone 4 cycles of neoadjuvant chemotherapy after the orchidectomy. Subsequently, a retroperitoneal lymph node dissection by laparotomy was performed. General anesthesia was combined with epidural anesthesia to provide adequate peri- and postoperative pain management. During surgery, the patient required no extra opioids. After discharge to a surgical ward in the afternoon, the pain remained bearable; therefore, no additional pain medication was given throughout the day. A prophylactic dose of low-molecular-weight heparin was given in the evening to prevent venous thromboembolism. The patient woke up suddenly in the middle of the night with extreme abdominal pain. After physical examination, it was clear that the epidural block was completely absent. A new epidural top-up was administered, but most of the pain persisted. Secondary migration of the catheter was the most probable reason for the inadequate epidural block. A failure rate of 24.8% has been quoted in the literature for epidural analgesia in patients undergoing major elective abdominal surgery for cancer.3 According to national guidelines, the epidural catheter should not be manipulated for the first 10 hours after low-molecular-weight heparin administration due to the risk of an epidural hematoma. Therefore, it was decided to discontinue the epidural analgesia and switch to intravenous analgesics. After a bedside loading dose with fentanyl, patient-controlled intravenous analgesia with fentanyl was initiated. In addition, esketamine was started at a continuous infusion rate. Due to persistent pain, in the following hours both pump rates were incrementally increased preceded by a loading dose. After each increase, there was a temporary decrease in pain, but the pain soon returned. In the early morning, the infusion rates were 150 μg/h for fentanyl (with a bolus of 50 μg every 20 minutes) and 10 mg/h for esketamine, with minimal effect. Fortunately, at that time, the epidural catheter could be safely manipulated. The catheter was withdrawn 1 cm, and a new epidural dose was given with an immediate positive effect. The continuous epidural infusion was restarted and the patient-controlled intravenous analgesia with fentanyl was stopped. Esketamine was continued as a coanalgesic. Both epidural and intravenous analgesics could be discontinued at postoperative Day 3. Given the traumatic painful experience, the patient asked for clarification a few months after his surgery. A conversation with the involved health care workers was scheduled, and the experience was discussed in a calm and friendly manner. The main question remained why the intravenous opioids had so little effect on pain in this opioid-naïve patient. Therefore, a PGx analysis was offered to investigate whether any genetic polymorphisms could provide an explanation. The patient agreed, after which his blood was sent to the lab for DNA analysis. The examined genes and found genotypes involved in analgesic metabolism and pain signaling are presented in Table 1. Most analgesics are extensively metabolized in the liver by cytochrome P450 (CYP) isoenzymes. Genes encoding these enzymes are subject to genetic polymorphism, meaning they are highly variable, with allele distribution showing considerable differences between populations.4 Other genes of interest associated with postoperative pain management include the catechol-O-methyl transferase (COMT) enzyme, the opioid μ1 receptor (OPRM1), and adenosine triphosphate–binding cascade transporter.5 We will further elucidate the 3 found mutations in our patient below. COMT acts as a key metabolizing enzyme by regulating the reuptake and degradation of extracellular catecholamines.6 A widely studied polymorphism in the COMT gene is the COMT Val158Met polymorphism. This polymorphism results in a 3- to 4-fold decrease in the enzymatic activity in the Met carriers.7 In different studies, the Val/Val genotype was associated with more morphine consumption during the acute postoperative period compared to the other genotypes.8, 9 Genetic variants of the COMT enzyme influence the OPRM1 expression in the brain. It is hypothesized that this is secondary to changes in dopamine concentration and interaction with co-localized enkephalin, an endogenous opioidergic ligand. Animal studies have shown that a lower dopamine concentration in the brain results in an increased production of enkephalins, which ultimately leads to downregulation of OPRM1. According to this theory, the Val/Val genotype will lead to a decrease in OPRM1 expression.10 CYP2B6, together with CYP3A4, is responsible for the N-demethylation of ketamine to norketamine. Norketamine has a 3- to 5-fold reduced potency comparative to ketamine as an N-methyl-D-aspartate receptor antagonist.11 The intermediate metabolizer phenotype may result in a reduced breakdown of ketamine. Oxycodone is converted to noroxycodone via CYP3A4 and to oxymorphone via CYP2D6. Both noroxycodone and oxymorphone are then further converted to noroxymorphone by CYP2D6 and CYP3A4, respectively.12, 13 A small prospective study (n = 130) has shown that poor CYP2D6 metabolizers have significantly more need for oxycodone during the first 12 hours after elective major abdominal surgery.13 Having natural red hair is associated with a different tolerance for pain, an increased anesthetic requirement, and enhanced responses to opioid analgesics. Red hair is nearly always a result of a melanocortin-1 receptor mutation. The melanocortin-1 receptor is involved in immune modulation, but studies show that it also may modulate pain responses in general.14, 15 Second, venlafaxine is a weak inhibitor of CYP2D6 and CYP3A4, but also an inducer of P-glycoprotein (P-gp) transporter. It is a serotonin–norepinephrine reuptake inhibitor, mainly used for the treatment of major depressive disorder. The P-gp transporter is largely implicated in the brain-to-blood efflux of opioids, namely, morphine and oxycodone. Upregulation of the expression of P-gp at the blood–brain barrier may lead to increased tolerance to the antinociceptive effect of such drugs.16, 17 Furthermore, cannabis use could interfere with opioid metabolism. The most abundant cannabinoid in cannabis is tetrahydrocannabinol, while other less abundant cannabinoids that can be detected include cannabidiol and cannabinol. These 3 cannabinoids are known inhibitors of several CYP enzymes.18 To conclude, our findings as to why our patient experienced an unexpected weaker effect/higher need for the administered analgesics are described below. First, the most important finding from the PGx analysis in this case is the COMT 472GG genotype. Previous studies have shown that the 472GG genotyped patients have increased morphine requirements postoperatively. It is plausible that the need for other opioids is also higher in this setting, given the possible downregulation of opioid receptors as discussed above. On the other hand, the other 2 polymorphisms found are less clinically relevant in this case, but may be important in the treatment of this patient in the future. The intermediate CYP2B6 metabolism may lead to reduced degradation of esketamine, but nevertheless did not lead to a reduction of pain. It may even have contributed to the traumatic experience by enhancing anxiety, which is a known side effect of esketamine. Oxycodone was not given here in the acute postoperative setting, but in view of the intermediate CYP2D6 metabolism, the need for a higher dosage may have to be taken into account in future surgeries. Finally, the cofactors mentioned above also play a role in the perception of pain. It has been known for some time that people with red hair experience pain differently, and both the use of venlafaxine and cannabis can negatively influence the pain experience as described above. The direct inhibition of CYP2D6 by venlafaxine may even lead to a poor metabolizing effect in this case. Based on the combination of the genetic analysis together with the red hair characteristic and the comedication, we can provide a possible explanation for the fact that this patient had much more pain than usual. Although still in its infancy, this case may contribute to the debate on the use of PGx in (individual) pain medicine. When a patient responds differently to analgesics than expected for no apparent reason, the use of DNA analysis should be considered to detect an abnormal gene profile. This allows the therapy to be individually adapted to achieve better outcomes for these patients in the future. The complaint was settled without further measures, and the patient was happy to receive a genetic passport for medication that will help him and his doctors in future settings as well. The authors declare no conflicts of interest. The authors have no sources of funding to declare for this article. Data available on request from the authors.
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