Impact of CYP2D6 Pharmacogenomic Status on Pain Control Among Opioid-Treated Oncology Patients

Abstract

Background Several opioids have pharmacogenomic associations impacting analgesic efficacy. However, germline pharmacogenomic testing is not routinely incorporated into supportive oncology. We hypothesized that CYP2D6 profiling would correlate with opioid prescribing and hospitalizations. Materials and Methods We analyzed 61,572 adult oncology patients from 2012 to 2018 for opioid exposures. CYP2D6 metabolizer phenotype (ultra‐rapid [UM], normal metabolizer [NM], intermediate [IM], or poor [PM]), the latter two of which may cause inefficacy of codeine, tramadol, and standard‐dose hydrocodone, was determined for patients genotyped for reasons unrelated to pain. The primary endpoint was number of opioid medications received during longitudinal care (IM/PMs vs. NMs). Secondary endpoint was likelihood of pain‐related hospital encounters. Results Most patients with cancer (n = 34,675, 56%) received multiple opioids (average 2.8 ± 1.6/patient). Hydrocodone was most commonly prescribed (62%), followed by tramadol, oxycodone, and codeine. In the CYP2D6 genotyped cohort (n = 105), IM/PMs received a similar number of opioids (3.4 ± 1.4) as NMs (3.3 ± 1.9). However, IM/PMs were significantly more likely to experience pain‐related hospital encounters compared with NMs, independent of other variables (odds ratio [OR] = 5.4; 95% confidence interval [CI], 1.2–23.6; p = .03). IM/PMs were also more likely to be treated with later‐line opioids that do not require CYP2D6 metabolism, such as morphine and hydromorphone (OR = 3.3; 95% CI, 1.1–9.8; p = .03). Conclusion CYP2D6 genotype may identify patients with cancer at increased risk for inadequate analgesia when treated with typical first‐line opioids like codeine, tramadol, or standard‐dose hydrocodone. Palliative care considerations are an integral part of optimal oncology care, and these findings justify prospective evaluation of preemptive genotyping as a strategy to improve oncology pain management. Implications for Practice Genomic variation in metabolic enzymes can predispose individuals to inefficacy when receiving opioid pain medications. Patients with intermediate and/or poor CYP2D6 metabolizer status do not adequately convert codeine, tramadol, and hydrocodone into active compounds, with resulting increased risk of inadequate analgesia. This study showed that patients with cancer frequently receive CYP2D6‐dependent opioids. However, patients with CYP2D6 intermediate and poor metabolizer status had increased numbers of pain‐related hospitalizations and more frequently required the potent non‐CYP2D6 opioids morphine and hydromorphone. This may reflect inadequate initial analgesia with the common “first‐line” CYP2D6‐metabolized opioids. Preemptive genotyping to guide opioid prescribing during cancer care may improve pain‐related patient outcomes.

Personalized Medicine in Cancer Pain Management

“…From 2012 to 2018, Reizine et al examined 61,572 adult cancer patients for opioid consumption. They verified the findings of Soley et al on the pharmacogenomics effects of CYP2D6 in CPM and indicated that CYP2D6 genotype may identify cancer patients at higher risk of insufficient analgesia when treated with standard first-line opioids, such as codeine, tramadol, or standard dose hydrocodone [99]. In 174 advanced cancer patients receiving supportive treatment, Yennurajalingam et al examined the genetic characteristics associated with pain intensity, necessary daily opioid dosage, and pain response.…”

CYP2D6‐guided opioid therapy for adults with cancer pain: A randomized implementation clinical trial

“…However, the CYP2D6 ‐oxycodone response relationship is less clear, and recent data suggest that CYP2D6 may not influence clinical response to oxycodone 15 . A recent analysis of patients with cancer, most of whom were taking codeine, tramadol, or hydrocodone, found that compared to NMs, PMs or IMs had increased rates of hospitalizations secondary to pain and more often required non‐CYP2D6 metabolized opioids to manage pain 33 . Based on the totality of evidence, current clinical recommendations at UF Health are to avoid codeine, tramadol, and hydrocodone in PMs and IMs but no recommendations are provided for oxycodone.…”

A consideration of CYP2D6 genetic variations in the Ghanaian population as a potential ‘culprit’ for the tramadol ‘abuse crisis’

“…The analgesic efficacy of a drug describes how the drug is able to carry out its pain relief activity. For opioids, their pain-relieving effects is affected by pharmacogenomic associations [ 11 , 12 ] which makes certain groups of individuals have either sub-optimal analgesic effects or adverse drug events from normal therapeutic doses.…”

“…Although these opioids may also be metabolised by other enzymes such as CYP3A4/5, CYP2D6 is rather responsible for the important role of the conversion of these medications to their active metabolites such as in the case of codeine and tramadol to morphine and O-desmethyltramadol respectively. CYP2D6 is primarily responsible for conversion of parent compound to 5 -30%active metabolites such as in the case of codeine, tramadol, hydrocodone and oxycodone [ 11 , 19 ] Thus, alterations in CYP2D6 gravely influences the therapeutic outcomes of pain management using codeine, hydrocodone and tramadol.…”