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Try out PMC Labs and tell us what you think. Learn More. Use of perioperative opioids for surgical pain management of children presents clinical challenges because of concerns of serious adverse effects including life-threatening respiratory depression.
This is especially true for children with history of obstructive sleep apnea. This review will explore current knowledge of clinically relevant factors and genetic polymorphisms that affect opioid metabolism and postoperative outcomes in children. Within the past several years, an increasing of case reports have illustrated clinically important respiratory depression, anoxic brain injuries and even death among children receiving appropriate weight-based dosages of codeine and other opioids for analgesia at home setting particularly following tonsillectomy.
Several national and international organizations have issued advisories on use of codeine in pediatrics, based on CYP2D6 pharmacogenetics. We have discussed the pros and cons of alternatives to codeine for pain management. Although routine preoperative genotyping to identify children at risk and personalized opioid use for pediatric perioperative pain management is still a distant reality, current known implications of CYP2D6 pharmacogenetics on codeine use shows that pharmacogenetics has the potential to guide anesthesia providers on perioperative opioid selection and dosing to maximize efficacy and safety.
Respiratory depression is the most serious adverse effect of opioids as it could potentially lead to hypoxic brain injury and fatality 1. Opioids are responsible for fifty percent of postoperative respiratory failure events 2 , 3. In fact, in pediatrics, there has recently been multiple fatalities in children from the use of codeine which has turned our attention to the role of genetics, especially Cytochrome P family 2 subfamily D type 6 CYP2D6 and OSA in this regard 11 , In this review, we will discuss briefly the role of pharmacogenetics with respect to opioid induced respiratory depression, highlighting the implications of CYP2D6 genetics on codeine safety, pros and cons of alternatives to codeine, and the role of OSA as a major risk factor for opioid induced respiratory depression.
Codeine is a weak opioid that was endorsed by the World Health Organization as the second step on the analgesic ladder for cancer pain and has been used routinely for postoperative and for breakthrough pain in chronic sufferers. CYP2D6 metabolic pathway of common oral opioids resulting in biologically active metabolites. Depending on CYP2D6 metabolic activity poor, intermediate, extensive or ultrarapid metabolizing status varying levels of respective active metabolites from codeine, tramadol, hydrocodone and oxycodone are formed resulting in clinically unpredictable inter-individual variations in responses.
Oral morphine, hydromorphone and tapentadol are not affected by the CYP2D6 metabolic pathway. Codeine was mostly prescribed by otolaryngologists This left codeine coformulated with acetaminophen as the only opioid analgesic classified as a Schedule III controlled substance and cough formulations with codeine remain Schedule V under federal law 17 ; unlike their Schedule II counterparts, Schedule III regulations allow for verbal and facsimile prescribing to pharmacies as well as refills with the original prescription.
However, reports of fatalities in children from the use of codeine 18 , 19 have raised concerns about the safety of codeine use 20 - Variability in the clinical response to codeine prompted investigations into genetic variants or polymorphisms of CYP2D6. This enzyme is mapped to chromosome 22 at 22q An individual who has multiple copies of functional genes 24 , would have the Ultrarapid metabolizer UM phenotype. Genetic testing is commonly available for common CYP2D6 variants. An activity score is ased to each allele in the diplotype 0 for nonfunctional, 0.
The patient's predicted metabolizer phenotype, is defined by the sum of the two scores:. In , a fatality after codeine administration was reported in a healthy 2-year old boy given codeine two days after adenotonsillectomy. In , obesity, codeine toxicity and polypharmacology were implicated in the deaths of three obese children aged four to 10 years given codeine doses based on ideal body weight Restrictions were placed on use of codeine in children under the age of 12 years, after adenotonsillectomy procedures.
A recent review of the adverse event reporting systems data of children who had codeine or codeine-containing products by the FDA over past 50 years showed 64 cases of severe respiratory depression and 24 deaths mostly in children younger than 12 years of age In fact, several pediatric hospitals have elected to remove codeine from their formularies.
Acetaminophen and nonsteroidal anti-inflammatory drugs are good alternatives for treating mild pain, as they do not have the adverse effects of respiratory depression. Increased use of non-opioids like oral and intravenous formulations of acetaminophen and non-steroidal anti-inflammatory drugs, which do not have the respiratory depressant side effects may be good alternatives to codeine in children. Ibuprofen was found to be least as effective as acetaminophen with codeine for postoperative pain control in children after tonsillectomy and facial surgery, with no increased risks of bleeding 41 - Dexmedetomidine DEX sedation is a promising sedative agent and an adjunct to anesthetic regimen especially in patients with history of obstructive sleep apnea OSA 44 , Because of the increased risks with opioids in obese patients and those with OSA, DEX as an adjunct to anesthetic regimen may potentiate opioid analgesia with minimal additional respiratory depression.
Is tramadol an alternative? The authors found that tramadol achieved similar analgesia, with less potential for side effects However, studies have shown that children who are CYP2D6 PM have lower plasma concentrations of the active metabolite and analgesia compared to EM, and in 2D6 UM, plasma concentrations, analgesia and side effects are greater than in those who are EM 49 - There was also a recent case report of tramadol administration leading to respiratory depression in who was a CYP2D6 UM Hence, its safety needs to be further investigated before widespread use.
It has no active metabolites and mainly undergoes glucuronidation However pediatric data on the safety of this medicine is limited. Would oxycodone, a semisynthetic opioid, be a safer alternative to codeine for managing post-tonsillectomy pain at home setting? Oxymorphone is 14 times more potent than oxycodone The affinity of noroxymorphone at the opioid receptor is three- and fold higher than oxycodone and noroxycodone respectively.
In a postoperative setting, the CYP2D6 PM were found to have decreased oxycodone metabolism, and higher analgesic consumption Other adult studies in postsurgical patients and cancer patients detected clinical differences among the CYP2D6 genotypes 59 , CYP2D6 activity also correlated with oxycodone experimental pain assessment, with UM experiencing increased pharmacodynamic effects Oxycodone overdose by wrong dosing has been reported before However, our ongoing pediatric oxycodone pharmacokinetic and pharmacogenetic study in perioperative setting revealed that compared to PMs, IMs and EMs have higher oxymorphone concentration.
It has also been shown that like codeine, maternal oxycodone use also causes central nervous system depression in neonates, so oxycodone is unlikely to be a safer alternative in this clinical setting Hydrocodone is also a potential alternative for analgesia. It is about 12 times more potent at the opioid receptor than codeine 55 , and about half the clearance is via CYP2D6 and CYP3A4 , into an active metabolite hydromorphone, and norhydrocodone, respectively. Hence, although both hydrocodone and oxycodone undergo metabolism via CYP2D6 to active metabolites, their analgesic effects are not as variable as codeine's because the parent drugs are nor prodrugs, but themselves pharmacologically active.
One case report demonstrates the complex interplay between drug-drug interactions and pharmacogenomics. A developmentally delayed five year Somalian old child died after administration of high doses of hydrocodone for ear infection. On genotyping, she was found to be a CYP2D6 PM, and had low hydromorphone blood concentrations; but co-administration of clarithromycin a potent CYP3A4 inhibitor and valproic acid for seizures since birth, prevented hydrocodone metabolism leading to high hydrocodone levels Hence, the dose—toxicity relationship of the alternative opioids need to be further studied in the pediatric population.
Lastly, the use of an oral morphine elixir has been suggested by some as an alternative The prescribers and pharmacists need to be vigilant when prescribing oral morphine as it is available in many concentrations 69 , however, although there is extensive experience with intravenous morphine in children, there is little clinical experience and very limited comparative clinical data on safety and efficacy available for the oral formulation.
In summary, drugs such as morphine 0. Pediatric OSA is associated with high incidences of adverse outcomes with the use of opioid analgesics for post-tonsillectomy pain management. In addition to codeine, potentially other oral opioids metabolized by the CYP2D6 pathway such as tramadol, hydrocodone and even oxycodone, cannot be considered safe analgesics without appropriate precautions to manage post-tonsillectomy pain at unmonitored home setting especially in young children with sleep apnea. Though preoperative CYP2D6 genotyping study in children undergoing tonsillectomy is an option, it is not widely available and third party payers do not readily reimburse for the genetic tests despite the CPIC guidelines 40 and other evidences, we observed ificantly more adverse effects with codeine at home even when it was administered on as needed basis Unpublished Data: Sadhasivam, MD Preoperative CYP2D6 testing before prescribing around the clock codeine, hydrocodone, tramadol and oxycodone at home setting would be preferable as all are at least partially metabolized by CYP2D6 pathway Figure , especially in young children with OSA and other respiratory comorbidities.
Alternatively, using other analgesics i. An alternative and less expensive approach to routine preoperative CYP2D6 genotyping would be to use safer and non-opioid analgesics in young children. To maximize pain relief and safety, we have successfully used opioid sparing pain management at home setting following pediatric tonsillectomy.
Our current practice is summarized in Table 1. Despite our high annual volume of tonsillectomy, we have not seen any increase in incidence of inadequate pain control, postoperative bleeding or serious life threatening complications with the above pain management regimen in the last 3 years. Currently, robust evidence to change clinical practice based on underlying genetic risk factors, access to routine preoperative genotyping, affordability and payer coverage for genetic testing are limited.
As compelling evidence for personalization of perioperative care based on genetic risk factors e. CYP2D6 and codeine related deaths increases, there will be better adaptability of routine preoperative genotyping and coverage of such services by third party payers. For example, many third-party payers are covering perioperative CYP2D6 genotyping for prescription of oral opioids in our pediatric institution. In future, pharmacogenetic studies also need to be complimented by epigenetic, proteomic, transcriptomic, and metabolomic information to gain additional knowledge and insight to improving personalized care as these factors may influence clinical outcome measures.
Another need of pharmacogenomics research, especially in pediatrics, is genetic counseling. Genetic counselors help patients and their families understand and adapt to the medical, psychological, and familial implications of genetic contributions to clinical outcomes.
As we transition from single-gene testing and genetic counseling to a full genomic medicine approach, clinical implications will get more complex. As we routinely use the Global Positioning System to navigate maps and ro, in the future, it is anticipated that we will use a Genomic Prescribing System GPS to proactively identify underlying genetic risks and guide personalized care. To implement pharmacogenomic based clinical decision support, there is a need for more robust study des, independent validations, larger populations and robust statistical approaches.
Others have taken a more active stance by identifying the 2D6 isoforms in their patients. Current known implications of CYP2D6 pharmacogenetics on codeine use shows that pharmacogenetics has the potential to guide anesthesiologists on perioperative opioid selection and dosing to maximize efficacy and safety. The present consensus seems to be that avoiding codeine whenever possible is the safest strategy. Currently, personalized opioid selection and dosing for perioperative pain management is still a long way.
More studies are needed to improve genotype-based personalized perioperative care in children. A multimodal opioid-sparing analgesia strategy reduces the need for perioperative opioid use, and improves analgesia and reduces serious risks associated with opioids in children, especially at unmonitored home setting. It is high time to avoid codeine and possibly other stronger opioids metabolized via CYP2D6 pathway, especially in children with ificant co-morbidities such as OSA or ificant respiratory disease.
Genetic identification of known variant alleles that affect the pharmacokinetics or pharmacodynamics of opioid agents can enable anesthesia providers to better select the appropriate opioid and dosing regimen for an individual patient, instead of empirical selection and dosing escalation. Currently, personalized opioid selection and dosing for perioperative pain management is still a long way off. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
The authors have no financial disclosures. Conflicts of interest: Authors have no conflicts of interest. National Center for Biotechnology Information , U. Curr Opin Anaesthesiol. Author manuscript; available in PMC Jun 1. Vidya Chidambaran , M. Author information Copyright and information Disclaimer. Copyright notice. The publisher's final edited version of this article is available at Curr Opin Anaesthesiol. See other articles in PMC that cite the published article.
Abstract Purpose of review Use of perioperative opioids for surgical pain management of children presents clinical challenges because of concerns of serious adverse effects including life-threatening respiratory depression. Recent findings Within the past several years, an increasing of case reports have illustrated clinically important respiratory depression, anoxic brain injuries and even death among children receiving appropriate weight-based dosages of codeine and other opioids for analgesia at home setting particularly following tonsillectomy.
Summary Although routine preoperative genotyping to identify children at risk and personalized opioid use for pediatric perioperative pain management is still a distant reality, current known implications of CYP2D6 pharmacogenetics on codeine use shows that pharmacogenetics has the potential to guide anesthesia providers on perioperative opioid selection and dosing to maximize efficacy and safety.
Keywords: Analgesia, anesthesia, obstructive sleep apnea syndrome, opioids, Codeine, Pharmacogenetics, pharmacogenomics, polymorphism. Introduction Respiratory depression is the most serious adverse effect of opioids as it could potentially lead to hypoxic brain injury and fatality 1. Codeine and CYP2D6 A Codeine Metabolism Codeine is a weak opioid that was endorsed by the World Health Organization as the second step on the analgesic ladder for cancer pain and has been used routinely for postoperative and for breakthrough pain in chronic sufferers.
Open in a separate window. The patient's predicted metabolizer phenotype, is defined by the sum of the two scores: PM has an activity score of 0 IM has an activity score of 0.Pain tablets without codeine
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Alternative Analgesics to Codeine for Acute Pain