Opioid use disorder in pediatric populations: considerations for perioperative pain management and precision opioid analgesia

Abstract

Introduction:

Opioids are commonly used for perioperative analgesia, yet children still suffer high rates of severe post-surgical pain and opioid-related adverse effects. Persistent and severe acute surgical pain greatly increases the child’s chances of chronic surgical pain, long-term opioid use, and opioid use disorder.

Areas covered:

Enhanced recovery after surgery (ERAS) protocols, are often inadequate in treating a child’s severe surgical pain. Research suggests that “older” and longer-acting opioids such as methadone are providing better methods to treat acute post-surgical pain. Studies indicate that lower repetitive methadone doses can decrease the incidence of chronic persistent surgical pain (CPSP). Ongoing research explore genetic components influencing severe surgical pain, inadequate opioid analgesia, and opioid use disorder. This new genetic research coupled with better utilization of opioids in the perioperative setting provides hope in personalizing surgical pain management, reducing pain, opioid use, adverse effects, and helping the fight against the opioid pandemic.

Expert opinion:

The opioid and analgesic pharmacogenomics approach can proactively “tailor” a perioperative analgesic plan to each patient based on underlying polygenic risks. This transition from population-based knowledge of pain medicine to individual patient knowledge can transform acute pain medicine and greatly reduce the opioid epidemic’s socioeconomic, personal, and psychological strains globally.

1. Introduction

Children often experience uncontrolled acute surgical pain, which is associated with excess opioid use, misuse, chronic persistent surgical pain (CPSP), and loss of life. Each year, more than 10 million pediatric surgeries occur in the US with opioids being the mainstay of treatment for moderate to severe pain. Short-acting opioids such as morphine, hydromorphone, and fentanyl, while effective in some patients, do not provide lasting analgesia and contribute to adverse effects resulting in suboptimal surgical pain control. Despite receiving potent prescribed opioids such as oxycodone for more than one to two weeks at home,[1] an alarming 20-50% of children develop CPSP,[2] largely due to suboptimal immediate surgical pain relief, which is the single greatest risk factor for CPSP. More than 50% of surgical patients experience inadequate pain relief,[3–5] a statistic that is unchanged for more than 30 years,[6] as well as significant adverse opioid effects due to narrow therapeutic indices and unpredictable inter-individual responses. Serious risks, including life-threatening respiratory depression (RD) and death can occur. Other immediate adverse effects such as excessive sedation or postoperative nausea and vomiting (PONV), frequently delay recovery and prolong hospital stay.[7]

Significantly CSPS is the most common postsurgical complication following major inpatient surgeries, with severe acute postsurgical pain being the greatest risk factor.[2,8] Additional risk factors include demographics i.e. adolescence, higher BMI, the type of surgical procedure and concomitant psychological illnesses such as anxiety or depression.[9] Ten to 60% of surgical patients develop CPSP and 2 to 15% have severe CPSP leading to poor quality of life.[10,11] Uncontrolled severe surgical pain leads to prolonged opioid prescribing, increasing the likelihood of persistent opioid use and misuse,[12] overdoses, and deaths,[13,14] .[15] In addition, the long-term effects of CPSP and opioid dependence are heritable, [15,16] life-deteriorating, and preventable.

Opioid-related problems are associated with a public health crisis, substantial mortality, and costs: More than 259 million opioid prescriptions are given annually in the US—enough for every American.[17] Unfortunately, more than 2 million Americans have opioid use disorders (OUD), with more than 33,000 preventable opioid overdose deaths in 2017.[18]This increased further to 56,064 deaths in 2020 and 75,673 deaths in 2021.[19] The opioid-related premature fatality and non-fatality societal cost is estimated to be more than $500 billion per year,[20–22] making the opioid epidemic a national emergency.[23] Opioid abuse refers to both opioid medical misuse and nonmedical opioid use. The former is defined by opioid use that differs from the prescriber’s intent, either by higher doses, increased frequency, or concomitant use with other recreational substances such as alcohol. Nonmedical opioid use is characterized either by use without one’s prescription or use for recreational purposes.

The risk of opioid abuse is strongly associated with the dose and duration of opioid exposure,[24] genetics, and environment.[25,26] Opioid misuse often begins during adolescence.[27,28] The prevalence of prescription opioid misuse or dependence is as high as 26%.[29] Therefore, in the perioperative care of adolescence patients, an opportunity exists to introduce preventive interventions knowing there will be surgical opioid exposure.[27,30]

Poor postsurgical pain control and opioids can result in negative educational and vocational consequences in adolescents[31] and constitute a significant socioeconomic burden,[32–35] with the loss of decades of productive life.[36–39] Since 1980 deaths resulting from opioid overdose have increased 5-fold[40], a trend that was worsened by the COVID-19 pandemic[41] with a further increase of 37% in mortality during that time.[42]

There is an urgent and unmet critical need for safe and effective therapy in children. This will allow optimization of acute surgical pain relief, by utilizing enhanced pain management techniques to achieve the best possible outcomes, while also preventing the transition from acute to chronic surgical pain and thus consequent persistent opioid use/misuse.[43] Transformative and precision surgical pain and opioid management strategies, such as the use of pharmacogenomics to determine an optimal analgesic dose while minimalizing potential side effects, are critical to avoid these long-term and major negative consequences. A long-term goal should be to improve safety and efficacy of surgical pain control while reducing adverse effects and the epidemic burden of opioids in children undergoing major surgery.

Unfortunately safe, effective, and proactive interventions are lacking to prevent persistent opioid use and misuse in adolescents. However, methadone, a unique long-acting opioid and N-methyl-D-aspartate (NMDA) antagonist, offers sustained analgesia, while reducing opioid tolerance and risks of CPSP compared with short-acting opioids.[44] Recently, a study demonstrated that a methadone-based standardized enhanced recovery after surgery (ERAS) multi-modal analgesia protocol, consisting of four methadone doses, acetaminophen, NSAIDS and muscle relaxants, improved outcomes for PSF (Posterior Spinal Fusion) [45] with short hospital stays (2-3 days) and less prescribed opioids (4-7 days vs. 7-18 days).[1] Despite this improvement, 30-40% of adolescents experienced PONV, uncontrolled severe pain, excessive sedation from methadone, OD and CPSP after PSF, necessitating a personalized approach to using and dosing methadone to achieve better outcomes. [1]Combining pharmacogenomic data with this methadone protocol to develop and implement a personalized perioperative analgesia platform could transform and proactively improve safety and efficacy in pediatric patients, as it accounts for the pharmacokinetic (PK) and genetic factors that significantly influence pain.[46,47] Optimal acute pain management without or with reduced opioids could have a major public health impact by alleviating acute pain while mitigating risks of opioids.[23]

In the following sections we will review risk factors for OUD in children, the efficacy of current practices for surgical pain management, and the role of methadone in precision analgesia, which offers a tailored approach to pain management strategies, wherein individual patient factors including genetic, pharmacokinetic and other non-genetic factors are taken into account to optimize effectiveness and minimize risks.

2.0. Risk factors for opioid use disorder

2.1. Adolescents are the biggest misusers of prescription opioids

In neonates, dependence on prescription opioids can happen within 5 days.[58]; 5 days is typically the minimum duration of opioid exposure following major surgeries such as PSF. While appropriately prescribed opioids are important for acute surgical pain relief, healthcare exposure has been associated with an increased risk of opioid misuse in vulnerable adolescents. More frequent visits in childhood increase the chances of an initial opioid prescription. In addition, young adults with chronic illnesses or chronic pain, which are known to be associated with a higher likelihood of opioid use may be more likely to seek medical attention.[59] Adolescence is the time for preventive interventions in the setting of surgical opioid exposure,[27,30] yet effective, safe, and proactive precision interventions are lacking to prevent persistent opioid use/misuse in adolescents. The risk of opioid abuse is strongly associated with the dose and duration of opioid exposure,[24] genetics, and environment.[25,26] Clinical pharmacogenomics could potentially mitigate the risk factors for OUD, however real-world evidence remains scarce, especially in children. One avenue for exploration involves optimizing acute pain management without or with reduced opioids to mitigate opioid dependence and misuse risks.[23]

2.2. Prescription opioid misuse in adolescents, mental health, and impact of pandemic on opioid overdoses.

Postoperative persistent opioid use, misuse, OD (2.2-7.9%),[60–62] and CPSP (36%)[2] in adolescents are common (~30%); they are understudied, underrecognized and undertreated, thus worsening long-term outcomes.[58] Prescribing postoperative opioids in pediatric patients is associated with a 2.1-fold increased risk of OUD as an adult.[63] About 500,000 adolescents and ~14% of high schoolers misuse prescription opioids, and nearly 170,000 are addicted.[27,64,65] As a result, hospital and PICU admissions for opioid overdose in pediatric patients have substantially increased and deaths have tripled.[66] Mental health and opioid misuse worsened during the COVID pandemic, affecting adolescents disproportionately. Black teenagers had 3-fold increase in deaths due to opioid overdose in 2021 as compared to pre-pandemic years.[19,67] Even before the pandemic, in 2017, 769,000 (4.2%) adolescents misused prescription opioids, and ~1 in 24 adolescents needed treatment for SUD.[68] However, only 4% of adolescents with an OUD received treatment,[69] underscoring the importance of screening and referral to OUD treatment. Prescription drug misuse results in thousands of hospitalizations of adolescents per year. Oxycodone and methadone caused the most deaths in adolescents, yet methadone was not one of the five most commonly abused medications.[70] Early identification is critical to preventing opioid addiction in adolescents.[30] To reverse the opioid epidemic in children, pain management strategies should be reformed to include a focus on prevention of overdose and avoiding medication misuse, before they occur with proactive monitoring of adolescents for OD and CPSP for the first 3 months after surgery.

3.0. Paradigm shift towards proactive risk prediction and personalized methadone analgesia

A paradigm shift towards proactive and personalized care is needed to maximize the safety and efficacy of methadone and other opioids in children undergoing surgery. Importantly, this transformative approach will improve the current best outcomes with standardized ERAS,[45,71] which benefits only 60-70% of patients. This approach will benefit all patients while preventing and hopefully eliminating costly OD, misuse, overdose, and deaths.

3.1. Current reactive practices to manage surgical pain result in poor outcomes

In the last decade, multimodal analgesia with opioids, non-opioid analgesics, and muscle relaxants has been promoted to reduce opioid usage, minimize side effects, and facilitate earlier oral analgesic transition and hospital discharge.[72–75] Despite these advances and standardization of reactive practices including standardized ERAS, which involves managing pain or adverse events of opioids in response to symptoms once they have occurred, suboptimal pain relief and/or opioid-related adverse effects are still experienced by more than 50% of adolescents undergoing PSF and other major surgeries, despite receiving potent opioids (>80% use prescribed opioids for >1 week at home).[1] These adolescents are at higher risks for OD, persistent opioid use, and CPSP,[28] 20-50% of them develop CPSP[2] largely due to inadequate acute surgical pain control.[50,51] Preoperative pain and anxiety increase the risk for CPSP.[76] It has been reported earlier that 36% of adolescents developed CPSP following PSF and treatment with short-acting opioids.[2] Adolescents who develop CPSP have a high life-long risk for opioid use and misuse,[28] and a 65% risk of developing chronic pain as adults,[3,77–79] contributing to excess opioid use, addiction, and overdose deaths. Inadequate control of severe acute postoperative pain contributes to excessive opioid use increases the prevalence of OD and CPSP.[80] Children with chronic pain are often unable to perform activities of daily living,[38] have poor academic success,[36,81] experience social isolation, depression, and suicidal tendencies[82–84], that result in a high risk of overdose-related death.[85] Untreated chronic pain in children also increases the risks for chronic pain in adulthood[86] with a higher risk for continued opioid abuse and poor psychiatric functioning,[87,88] leading to a loss of productivity, a lower quality of life, and an unsustainable socio-economic burden.[89–92] Higher inpatient opioid use predicts larger opioid prescriptions at discharge, and larger discharge prescription predicts greater post-discharge opioid use and misuse.

3.2. Methadone – an old drug and a novel multidose strategy to enhance lasting analgesia, reduce overall opioid need, improve safety and reduce CPSP in children

Methadone is a long-acting opioid and NMDA antagonist,[93] with less sedation and lower abuse potential compared with morphine.[94] Methadone reduces opioid tolerance and opioid-induced hyperalgesia, and risk of CPSP.[97] Intraoperative methadone has been used for surgical pain relief for a few decades.[98] During the last decade, reinvigoration of the use of intraoperative methadone^[99] has slowed due to fear of serious adverse effects including RD and inconsistent analgesia.^[100,101] Even a single intraoperative methadone dose reduced opioid requirement, pain scores[102] and persistent analgesic benefit for 3 months following spine surgery in adults.[44] Standardized multidose methadone reduced opioid need by ~40% and lowered the CPSP risk in 60-70% of children.[45,71] Yet, 30-40% of (high-risk) patients on standardized ERAS protocols still experience severe surgical pain, opioid-adverse effects, OD and CPSP due to huge inter-child variability with perioperative methadone, and genetic predispositions to opioid adverse effects.

3.3. Analgesic efficacy of perioperative methadone

Methadone has been used for surgical analgesia effectively in children[45,103,104] although its safety and optimal dosing remain inconclusive in children. Safety of a single intraoperative dose of methadone,[105] beyond 0.3 mg/kg has not been established.[100,106] In adolescents undergoing PSF, single-dose methadone resulted in only minimal or no reduction in total opioid use without sustained analgesia.^[73,101,107] This is because of rapid redistribution after IV administration despite a long half-life.[108] Thus, a single dose in adolescents can result in suboptimal analgesia irrespective of the dose administered[101] with the plasma concentration dropping below analgesic concentration in <1 hour^[108] resulting in the need for additional doses.[108,109] As a long-acting opioid with lasting analgesic efficacy and minimal abuse potential, precisely dosed methadone could be a safer and better alternative for short-acting opioids, typically characterized by a relatively quick onset of action and short duration of analgesic activity. Leveraging its extended duration of action, methadone can provide more sustained analgesia, thereby reducing overall opioid consumption and function as an “opioid-sparing opioid”.

3.4. Improvement with standardized methadone ERAS protocol in adolescents is only incremental and does not benefit all children

A single larger dose of intraoperative methadone in adolescents had a high incidence of RD (29% on day 1 and 38.7% on day 2) after PSF.[101] We published that standardized methadone-based multimodal analgesia had the best-in-class outcomes: the shortest reported length of stay (LOS), reduced inpatient opioid use, earlier bowel movement, reduced post-discharge pain-related phone calls[45] without any RD compared with a single large intraoperative dose of methadone in adolescents.[73,101,107] However, despite standardized methadone ERAS protocol, 30-40% of PSF adolescents experienced PONV, excessive sedation, poor control of acute surgical pain, CPSP and OD requiring additional interventions from clinicians despite non-toxic mean analgesic methadone concentrations. A proactive and personalized transformative approach will significantly improve safety, efficacy, and LOS in adolescents, and has the ability to be significantly better than the standardized weight-based methadone ERAS analgesia.

4.0. CYP2B6 genetic variations, methadone PK, and clinical outcomes in children

CYP2B6 is the most significant enzyme mediating the stereo-selective metabolism of methadone.[110,111] CYP2B6 expression shows 20-250 fold variability.[112] Variants in CYP2B6 significantly impact methadone PK in non-surgical adult patients.[113–115] CYP2B6*6/*6 was associated with lower clearance in S- and R-methadone compared with wild type, *1/*1, in 64 non-surgical adult volunteers taking a single methadone dose.[113] The frequency of *6 haplotype varies in European Americans (14-27%) and African Americans (33-50%).[113] CYP2B6 polymorphisms influence methadone maintenance therapy (MMT) methadone dose needs.[116–118] For methadone dosing in non-surgical adult patients, a multivariate model including CYP2B6 genotype, sex, and BMI was suggested.[119] For the first time in surgical patients, our pilot study showed that CYP2B6 variants correlated with methadone’s clearance, pain and PONV.[120] [121]

4.1. Oxycodone, OD and OUD in adolescents

Oxycodone is the most commonly used and abused prescribed opioid resulting in OUD and overdose deaths in adolescents.[122] Opioid misuse and dependence among patients prescribed opioids in the US is high and increasing, with a prevalence of OD among outpatients as high as 26%.[29] Childhood abuse, African-American ancestry, and conduct disorder have been reported to be associated with rapid development of OD in children.[123] We showed earlier that fatty acid amide hydrolase (FAAH) genetic variants are associated with higher risks of opioid-related RD. Interestingly, the same FAAH variant (rs324420)[124–128] is strongly associated with street drug dependence and abuse, highlighting the importance of opioid-endocannabinoid pathway interactions. This could potentially explain increased mortality[129] and morbidity[130,131] in infants exposed to substance abuse including cannabinoids during the perinatal period and in individuals abusing opioid agonists and/or cannabinoids (e.g., marijuana, synthetic cannabinoids).,[132–137] . With OUD, the onset of opioid use at age <18 y was found to have higher odds of having a psychiatric comorbidity compared with older patients (>30 y) (odds ratio 2.94, P=.02). Understanding the risk posed by an earlier onset of opioid use for the later development of comorbidity informs clinical practice and stresses the need for early identification of adolescents at high-risk.[138] There is a paucity of critical knowledge to address OD and OUD in adolescents undergoing surgery. There is an urgent need for studies examining prescription opioid use with specific and validated proposed tools, Opioid Risk Tool [139] and Overdose Risk Behavior Scale,[140] to proactively identify adolescents at risk for OD and OUD.

4.2. Recognizing risk factors for OUD in children and sources of obtaining opioids

There are multiple risk factors that predispose children and adolescents to OUD. Some significant risk factors for prescribed opioid use include white non-Hispanic race and ethnicity, adolescence, medical insurance poor general health, and residing outside the Northeastern region in the US.[141] Genetic predisposition also plays a part as demonstrated by population-based twin study[142], which has found a common genetic factor to have strong influence for opioid abuse.. Further genomic studies [143,144] have identified specific polymorphisms that may be linked to OUDs. Access to prescription medication and younger age of initial exposure also seem to be of great importance. Many children who developed OUD were initially appropriately prescribed opioids. Children less than 13 years of age at the time of first encounter with opioids have been associated with a greater likelihood of prescription drug abuse and dependence.[145] Psychiatric disease is also linked to OUDs in adolescents and young adults. Welsh et al. (2017) reported that adolescents and young adults with OUD were over twice as likely to have an anxiety-related diagnosis, and over three times as likely to have Generalized Anxiety Disorder.[146] Depressive disorders and externalizing behavior disorders, characterized by uncontrolled, impulsive, or aggressive tendencies, such as attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder, and conduct disorder are also associated with opioid misuse. [147]

A recent survey discovered that more than half of adolescents and young adults who misuse opioids acquired these prescription drugs through friends and family. Frequent concomitant use of other recreational substances such as cocaine, hallucinogens, heroin, and inhalants has also been reported in these groups. Consequently, clinicians should therefore consider screening adolescents and young adults with opioid misuse for concurrent substance abuse and offer intervention programs, ranging from therapy to pharmacotherapy, if applicable.[148]

4.3. Enhancing pediatric post-surgical outcomes through genetic predictors and proactive opioid risk prevention

Opioids are responsible for the numerous adverse reactions in hospitalized patients (16%) and outpatients with a high risk of death and anoxic brain injury from opioid-induced respiratory depression.[149,150] Opioids also have varying analgesic efficacies and toxicity thresholds. Based on earlier studies on genetic predictors of severe pain and opioid-adverse outcomes,[151–154] supportive literature from others[44,100,155,156] and our recent success in obtaining improvedpost-surgical pain and opioid outcomes in adolescents following PSF,[45,71] we propose the next step to further improve outcomes: the introduction of a proactive pain and opioid risk prediction tool and prevention with precision analgesia, based on genetic predictors, to deliver and enhance surgical pain relief and avoid opioid-related adverse outcomes and CPSP in pediatric patients.

4.4. Methadone pharmacokinetics

All prior multidose methadone PK and genetic studies were performed in the stable context of MMT for OUD or adult volunteers, but not in acute surgical settings which doubles the level of alpha 1-Acid glycoprotein (AAG), an acute-phase protein found in plasma, capable of binding to medications such as methadone. Surgical stress increases AAG levels, which binds 90% of methadone and significantly alters perioperative methadone’s PK.[71]17-fold inter-individual variation in clearance affecting blood methadone levels, [157] contributes to the varying dose requirements for MMT.[116,158] Oral bioavailability of methadone is approximately 75%,[157] with mainly hepatic CYP2B6[111] metabolism and about 10-20% of methadone is eliminated in urine.[159] Other enzymes involved include CYP3A4, CYP2D6, CYP2C9 and CYP2C219.[160,161] Methadone is metabolized to two major inactive metabolites, 5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP), which are both detectable in urine.[162] Methadone is available as a racemic mixture consisting of equal parts of the active R-enantiomer and the inactive S-enantiomer.[110] CYP2B6 metabolizes S-methadone faster than R-methadone.[160] The elimination half-life for R- and S-methadone in adults has been shown to be 52 and 38 hours respectively, but shorter in children; with 34 and 24 hours respectively.[163] CYP2B6 variants affect oral methadone greater than IV methadone (due to first pass metabolism) and multi-dose regimens more than a single dose (due to CYP auto-induction by methadone).[113] At present there is no multidose methadone PK and genetic study in pediatric or adult surgical populations on Pubmed. We recently published methadone’s PK in children based on a novel multi-dose strategy,[164] pharmacogenetics of methadone[165] and pilot work on CYP2B6 and AAG affecting perioperative methadone[71,120,166] to lay the foundation to maximize methadone’s safety and efficacy with precision dosing.

Before concluding we will briefly mention how and when methadone is currently considered in the pharmacologic treatment of OUD in pediatric patients.

4.5. Role of methadone in OUD in children

Buprenorphine (partial opioid agonist) and naltrexone (opioid antagonist) are the most frequently used medications by pediatricians in the outpatient treatment of OUD in children and adolescents. Methadone is sometimes considered a second-line pharmacotherapy for OUD in pediatric patients.[167] Methadone clinics in the United States must obtain a special waiver at the federal level in order to provide treatment to children.[168] Children under 18 years of age need to demonstrate two treatment failures of detoxification or psychosocial interventions without pharmacotherapy to be eligible for treatment with methadone.[169] Despite this, a small retrospective study of 61 heroin-using youth found that methadone demonstrated better retention rates compared with buprenorphine, leading to a need for further investigation as to the utility of methadone for OUD in younger patients.[170–172] Studies performed in adults also corroborate this finding, even though at higher doses the differences in suppressing illicit opioid use between methadone and buprenorphine were less pronounced.[173]

5.0. Summary

Opioids are well-established in the management of perioperative pain. A large percentage of children currently experience significant adverse effects and uncontrolled pain due to narrow therapeutic indices and unpredictable inter-individual responses. Serious risks, such as respiratory depression and death, and other adverse effects, such as excessive sedation and postoperative nausea and vomiting, are detrimental to the recovery of children and can prolong hospital stays. Uncontrolled immediate surgical pain predisposes to CPSP which can easily lead to opioid misuse and dependence. Short-acting postoperative opioids can rapidly lead to dependence in children in a matter of days. Long-term effects of CPSP and opioid dependence (OD) are heritable, life-deteriorating, and preventable.

There is a pressing critical need for a safe and effective therapy in children that can optimize acute surgical pain relief while preventing the transition from acute to chronic surgical pain and persistent opioid use/misuse. The long-term goal is to improve the safety and efficacy of surgical pain control while reducing opioid adverse effects and the opioid epidemic burden in all children.

Standardized ERAS protocols are still reactive, benefit only 60-70% of children, and do not maximize the safety and efficacy of surgical pain management. Proactive risk prediction and precision ERAS analgesia successfully overcome the current unmet clinical needs, inadequacies of the standardized ERAS protocols, single gene-based PK and outcome associations. Using this approach, precision perioperative analgesia can be provided in all children by utilizing robust polygenic-biopsychological biomarkers-based risk predictions of OD and CPSP, for the best post-surgical outcomes. This enables the precise personalization of analgesia in children, which will reduce acute surgical pain, opioid use, and adverse effects in millions of children each year. It will also delineate the impact of multi-genic and non-genetic factors on the huge inter-child variability in susceptibility to CPSP, OD, and persistent opioid use in vulnerable adolescents.

6. Expert opinion

Opioids are often used as a mainstay of pediatric surgical pain management. Unfortunately, the efficacy and side effect profile of opioids cause significant physical, phycological, and socioeconomic implications. While opioids were once thought to be excellent analgesic medications, their efficacy in surgical pain management varies widely. Up to 50% of children have inadequate post operative pain relief. Children who suffer intense post operative pain are then at increased risk of chronic persistent post-surgical pain as high as 35% following posterior spinal fusions[3–5].

Inadequate acute post operative pain management will likely lead to long term opioid prescriptions to manage ongoing persistent pain. This prolonged use of opioids, especially in adolescents, greatly increases their risk of opioid use disorder. Despite good intentions, appropriate post operative opioid prescriptions are often the initial step in the pathway leading to opioid use disorder. The struggle with opioids is that some children show great analgesic response and do not have complications, while other children, despite appropriate dosing, suffer from intense pain and opioid addiction. Risk factors for children vary from socio-economic factors such as adolescence and geographic location. Medical conditions such as psychiatric diseases and behavior disorders also contribute to increased opioid abuse. Finally, studies indicate that genetics play a significant role in opioid abuse. Further studies are required to deepen our understanding of the genetic implications associated with opioid therapy. These studies have the potential to introduce novel “game-changing” approaches to post operative pain management and thereby drastically decrease the impact of the opioid epidemic.

The ability to provide a proactive and individualized approach to perioperative pain management using the patient’s own genomics as a guide can transform pain medicine. Until we acquire a better understanding of the genetic component of opioid therapy, we are left with the commonly used opioids. One opioid that shows new promise is methadone. Methadone is being used successfully in posterior spinal surgery to decrease chronic pain. While the optimal dosing remains elusive, repetitive small dosing at set intervals shows promise.

Unfortunately, opioid use disorder in adolescents continues to be a major health problem. Not only does society have to protect children from addiction and abuse, but also provide treatment to those who suffer from opioid use disorder. Once a child is determined to have an opioid use disorder, prompt and aggressive intervention can be lifesaving. Unfortunately, many of these children go unrecognized, and even once abuse and addiction are recognized, treatment facilities are lacking in number. Only 4% of adolescents receive treatment for opioid use disorder. For society to handle the opioid pandemic more effectively, the availability of treatment centers must increase and the stigma around opioids must stop. In addition, further barriers to treatment such as inadequate professional education, regulatory hurdles and limitations in public and private health insurance coverage need to be addressed.

A concerted effort is needed to better understand opioid pharmacogenomics, improve perioperative pain management, and decrease opioid use disorder risk factors to help battle the ongoing opioid pandemic. Additionally, if children succumb to opioid use disorder, prompt and aggressive treatment needs to be readily available to return the child to their pre-disorder state.

Article highlights.

• Opioids are used for post-surgical pain, yet children still suffer from severe pain and numerous adverse effects of opioids.

• There are many risk factors that predispose a child, especially an adolescent, to opioid use disorder including medical, psychological, socioeconomic, age of first opioid exposure, genetics and environment.

• Methadone, an old long-acting opioid and an opioid-sparing opioid, is showing new promise towards decreasing chronic post-surgical pain.

• New research is uncovering the effects of a patient’s genetic composition, glycoprotein variations, and CYP2D6 polymorphisms have on the efficacy and adverse effects of opioids. As our knowledge of pharmacogenomics increases, the ability to individualize perioperative analgesia can transform pain medicine.