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Age-Specific PK/PD in Pediatric Analgesic Administration
Managing pain in pediatric patients involves understanding the developmental variations in drug metabolism and the effects of medications. It also requires the use of multiple classes of analgesics.
In infants and young children, drug dosing is typically extrapolated from adult and older child data using weight-based scaling due to limited pharmacokinetic (PK) and pharmacodynamic (PD) studies in this age group. However, the PK/PD properties of analgesics change with age; drug responses in infants and young children are distinct from those in older children and adults. The elimination half-life of many analgesics is longer in neonates and young infants due to their underdeveloped liver enzyme systems. Moreover, the clearance of analgesics can vary among young children. Within the first few weeks of life, renal blood flow, glomerular filtration, and tubular secretion increase significantly, reaching near-adult levels by three to five months. Toddlers and preschool-aged children often have a higher renal clearance of analgesics compared to adults, while clearance is decreased in premature infants. Additionally, age-related differences in body composition and protein binding are present. Neonates have a higher total body water ratio to body weight than older children and adults. High-perfusion tissues like the brain and heart make up a larger percentage of body mass in neonates than lower-perfusion tissues like muscle and fat. Neonates also exhibit decreased serum levels of albumin and α1-acid glycoprotein, leading to lower protein binding of some drugs and subsequently higher levels of free, active drug.
Two-Step Approach to Pharmacologic Management of Cancer Pain in Children
In 2012, the World Health Organization (WHO) expanded its guidelines on cancer pain relief and palliative care to include all children with medical conditions causing ongoing tissue damage or inflammation. This update introduced a two-step approach to the pharmacologic management of pain in this demographic. For mild pain, the recommended first-line treatments are acetaminophen (paracetamol) and/or NSAIDs such as ibuprofen. For moderate to severe pain, opioids are prescribed. Previous guidelines suggested an intermediate step using weaker opioids like tramadol and codeine. However, due to the limited labelling of tramadol for children under 12 and its scarce availability internationally, along with the variable efficacy and potential toxicity of codeine due to CYP2D6 polymorphism, this step has been omitted.
The revised WHO approach aligns with the European Association for Palliative Care’s endorsement of this method. While managing cancer-related pain in children with this two-step strategy, it is essential to consider the side effects of NSAIDs, such as potential platelet dysfunction leading to increased bleeding risks, particularly concerning in patients where bleeding could be exacerbated by disease or treatment. Moreover, prolonged NSAID usage may impair renal function, adding to the renal toxicity risks from other chemotherapy and supportive care medications. NSAIDs might also reduce the renal clearance of certain chemotherapeutic agents, including methotrexate.
Given these risks, acetaminophen is often preferred for mild pain management in children prone to or experiencing thrombocytopenia. Effective doses are typically 15 mg/kg every six hours. For children unable to take oral medications, IV formulations of acetaminophen are available, although these can be expensive. Usage limits for acetaminophen are especially important in cases of liver dysfunction or failure.
Acetaminophen and ibuprofen also serve as antipyretics, so they are commonly prescribed as needed (PRN) to avoid masking fevers, which could indicate infections. Consequently, for persistent pain, opioids are administered on a scheduled basis.
NSAIDs and aspirin work by non-specifically inhibiting cyclooxygenase (COX) enzymes, COX-1 and COX-2, which are involved in prostanoid production from arachidonic acid. COX-1 is constitutively expressed in several tissues, including platelets and the gastric mucosa, while COX-2 is inducible and up-regulated in response to inflammation and injury. COX-1 inhibition is associated with many of the adverse effects of NSAIDs, whereas COX-2 inhibition is primarily responsible for their analgesic effects. COX-2 inhibitors (coxibs) are generally considered safer than non-selective NSAIDs due to reduced gastric bleeding and lack of effect on platelet function. However, renal toxicity remains a concern, although thrombotic risks such as stroke or myocardial infarction, prevalent in older adults, are not considered elevated in pediatric cancer patients.
Topical NSAID therapies, which are easier to administer and have specific pharmacologic advantages, are under-explored in children, particularly those with cancer. Despite this, the WHO guidelines do not exclude the initial use of strong opioids for treating moderate to severe pain effectively. A study comparing non-opioid analgesics to strong opioids in adults with advanced cancer indicated that starting treatment with strong opioids resulted in better pain management outcomes and higher patient satisfaction without significant adverse events.
Opioid Analgesia in Pediatric Cancer Patients
In pediatric cancer pain management, commonly used μ-opioid agonists include morphine, hydromorphone, and fentanyl. Patient-controlled analgesia (PCA) is viable for children as young as five, depending on cognitive development. Less data is available on other opioids like sufentanil, hydrocodone, oxycodone, methadone, and buprenorphine, making morphine, hydromorphone, and fentanyl the preferred choices based on extensive clinical experience and evidence. Various delivery systems, including transmucosal and transdermal methods, offer alternatives to injection, which can be particularly beneficial in pediatric settings to minimize pain and fear associated with needle use.
Atypical Opioid: Tramadol
Tramadol is an atypical opioid that exhibits weak affinity for the μ-opioid receptor and also acts as a mild inhibitor of serotonin and noradrenaline reuptake. A notable benefit of tramadol is its relatively lower risk of inducing respiratory depression compared to many other opioids, although it carries a black box warning due to potential respiratory depression if dosages exceed the patient’s metabolic and elimination capacities.
Tramadol is metabolized in the liver and excreted by the kidneys, considerations that are crucial when it is prescribed alongside nephrotoxic or hepatotoxic drugs. Similar to codeine, tramadol is a prodrug that is converted into its active metabolite, O-desmethyltramadol. The use of tramadol in pediatric populations has come under scrutiny. The U.S. Food and Drug Administration (FDA) has issued a boxed warning and contraindicates its use in children under 12 years for any reason, and in children under 18 years following tonsillectomy or adenoidectomy. Additionally, the European Medicines Agency (EMA) has released strong warnings about the variable metabolism of tramadol and advises against its use in children with compromised respiratory function and in postoperative settings.
Adverse Effects of Opioid Analgesics
General
Opioid analgesics can cause a variety of adverse effects in both opioid-naïve and opioid-tolerant patients, including somnolence, constipation, pruritus, nausea, vomiting, urinary retention, and hyperhidrosis (excessive sweating). Long-term opioid use may also affect immune function and testosterone levels in adults, although the implications of these effects in children remain uncertain. Effectively managing these side effects is crucial for pediatric cancer patients.
Constipation
In cases where opioids are used for prolonged periods or at high doses to manage CNS pain, incorporating a bowel regimen into the treatment plan is essential to mitigate the risk of constipation. This risk can be exacerbated by chemotherapeutic agents like vincristine, which slow gut peristalsis. For opioid-induced constipation that does not respond to standard laxatives, peripherally acting μ-opioid receptor antagonists such as subcutaneous methylnaltrexone and oral naloxegol are approved for use in adults and are sometimes used off-label in pediatric cancer patients.
Pruritis
Pruritus is another common side effect of opioid therapy. While antihistamines are often prescribed for pruritus, they may cause sedation and other mental status changes, particularly at high doses or when combined with other anticholinergics or opioids. Other treatments for pruritus include low-dose opioid antagonists, κ-opioid agonists, 5-HT3-receptor antagonists, and antidepressants.
Urinary Retention
Urinary retention, another potential opioid side effect, can be particularly problematic in patients treated with oxazaphosphorines like ifosfamide and cyclophosphamide, which may cause hemorrhagic cystitis. It is crucial to monitor intake and output closely in these cases.
Dependence and Addiction Concerns
Concerns about the risk of dependence and addiction can hinder the use of high-dose or long-term opioid therapy in children. Although addiction fears are prevalent, addiction itself is a complex psychopathology and does not typically arise from the medical use of opioids in patients who are not predisposed due to genetic, psychiatric, or socioeconomic factors. It is rare in the pediatric population. However, opioid misuse and abuse may occur in older adolescents with complex psychosocial issues, which may serve as maladaptive coping mechanisms for pain. While misuse and abuse can be precursors to addiction, they do not necessarily indicate addiction. The rise in prescription opioid abuse and related fatalities has led to stricter prescribing regulations.
The concept of pseudo addiction should also be considered. This phenomenon, often observed in cancer patients, involves behaviours similar to those of addiction (such as clock-watching and drug-seeking) that result from the undertreatment of pain. These behaviours are typically due to clinicians prescribing opioids at inadequate doses or intervals. The American Society of Clinical Oncology (ASCO) advises clinicians to understand terms such as tolerance, dependence, abuse, and addiction as they relate to opioid use and to apply universal precautions to reduce the risk of abuse, addiction, and adverse outcomes.
Understanding Tolerance to Opioids
Tolerance, dependence, and the risk of withdrawal from opioids do not imply addiction. Rather, they are pharmacologic consequences that occur with the appropriate medical use of opioids over several days to a week. These effects are similar to those seen with many other pharmacologic substances, such as insulin, beta-agonists, and many diuretics. Generally, if a patient shows tolerance to opioids, it’s safe to assume they are also dependent and at risk of experiencing withdrawal symptoms, or opioid abstinence syndrome, if the opioids are abruptly discontinued or tapered too quickly.
Common symptoms of withdrawal in children who have developed tolerance and dependence include severe dysphoria, diarrhoea, abdominal cramps, nasal congestion, and behavioural symptoms such as anxiety and restlessness. The manifestations of withdrawal in young children can differ from adults—for instance, an infant may exhibit a high-pitched cry and show inconsolability with a pacifier, bottle, or swaddling, while a toddler may show signs like diarrhoea and temperature instability.
Preventing and Managing Opioid Tolerance in Pediatric Patients
To manage tolerance to opioid analgesics and maintain their clinical effectiveness, various strategies can be employed for children who require prolonged high-dose opioid therapy. One effective approach is the use of N-methyl-d-aspartate (NMDA) antagonists such as methadone concurrently with opioids. Methadone is beneficial for its dual action as both a μ-opioid receptor agonist and an NMDA receptor antagonist, which helps minimize the development of opioid tolerance. When managed carefully by experienced clinicians, rotating patients from other opioids to methadone can be a safe and effective strategy for managing cancer pain and mitigating the side effects of opioid tolerance.
Buprenorphine, a semisynthetic opioid available in various forms including sublingual and oral tablets, injectable solutions, transdermal patches, and oral films, also plays a role in the management of opioid tolerance. It has a complex pharmacodynamic profile and is a partial μ-opioid agonist with a slow dissociation from the receptor, which gives it antihyperalgesic properties and a ceiling effect for respiratory depression but not for analgesia.
Ketamine, used at subanaesthetic doses ranging from 0.1 to 1.0 mg/kg/h, has shown efficacy in managing opioid-induced tolerance and severe side effects like profound sedation in pediatric cancer patients. Combining ketamine with opioid analgesics such as morphine, methadone, and hydromorphone has been reported to improve pain control significantly.
Common analgesic dosing and instructions:
