23 Prevention and Treatment of Pain in Children with Serious Illness

Stefan J. Friedrichsdorf, Lauren Heathcote, Michael Sangster, Donna Eull, and Amber Borucki

Family Reflection

Introduction

Pain in Children with Serious Illness

Pain is among the most distressing and most prevalent symptoms children with serious illness experience in their disease trajectory and especially during their end-of-life period.¹ Most published data stem from children with cancer and show a significant symptom burden in this population.^2,3,4,5 Self-reports from children with malignancies show high distress from pain in 39% of pediatric patients with advanced cancer, which increased to 58% at end of life.⁵ Children who were enrolled into North American pediatric palliative care (PPC) programs experienced on average eight additional distressing symptoms other than pain.¹ In these patients with advanced serious illness, the majority of distressing symptoms, such as unrelieved pain, were not treated during the end-of-life period, and, when treated, the therapy was commonly ineffective.^2,3,4,5,6,7

Multimodal Analgesia

Advanced pain treatment and prevention for children with serious illness usually requires multimodal analgesia, which means, based on the individual patient, combining multiple analgesic agents (such as basic analgesia, opioids, adjuvant analgesia), regional anesthesia, rehabilitation, and psychological and integrative (previously called “nonpharmacological”) therapies which act synergistically for more effective pain control with fewer side effects than a single analgesic or modality.^8,9,10

Analgesic medications, especially opioids, remain the foundation of advanced pain treatment in children with serious illness. However, the past few years, and promoted by PPC curricula,¹¹ have brought a paradigm shift away from “medications-only” toward offering “multimodal analgesia,” as a large number of children with complex pain do not achieve adequate analgesia solely with pharmacology.

Figure 23.1 shows the components of multimodal analgesia, with the implication that an individual child may require one, several, or all of the components listed in each circle to achieve excellent analgesia. Each of these therapeutic options is described later in more detail.

Pain in Nonverbal Children with Impairment of the Central Nervous System

While nearly all published PPC data come from children with malignancies, the majority of children with serious illness in high-income countries do not have cancer, but metabolic, genetic, or neurologic diseases with impairment of the central nervous system (CNS), which usually leaves them nonverbal.^1,7 Assessing pain may be complicated in these children by possible altered pain processing,¹² and validated multidimensional observational tools are available.¹³ Frequently used tools in this population include the revised Face, Legs, Activity, Cry, Consolability (r-FLACC),¹⁴ Pediatric Pain Profile (PPP),^15,16 or Noncommunicating Children’s Pain Checklist-revised (NCCPC-R).¹⁷

Pinpointing the correct underlying pathology causing pain in nonverbal pediatric patients with impairment of the CNS remains a challenge for clinicians and caregivers alike. The pain experience may be driven by the underlying disease, comorbidities, and/or painful procedures and interventions. In addition to the pain pathophysiologies discussed here (acute, chronic, total, neuropathic, and/or visceral pain) many children receiving artificial hydration and nutrition via feeding tubes may also develop feeding intolerance and visceral hyperalgesia, and their clinical course may be further complicated by spasticity/contracture, reflux, medication withdrawal, hypoactive or hyperactive delirium, dysautonomia, and/or nausea. Of note, autonomic stress responses, including, changes in blood pressure, heart rate, temperature, respiratory rate, and epinephrine/norepinephrine serum levels, do not usually correlate with severity of pain.¹⁸

Prevention and Treatment of Pain and Anxiety Caused by Needles

A majority of children and their families report needle pain as the worst pain experienced in the hospital setting.^19,20 Children with complex illness and PPC needs are at high risk for frequent exposure to needle procedures in the course of diagnosis and treatment. To prevent emotional trauma and other long-term effects of poorly managed pain in this vulnerable population, it is essential for all healthcare providers to make every effort to prevent and treat needle pain effectively. Untreated needle pain caused by procedures such as blood draws, injections, and venous cannulation can have long-term consequences including needle phobia, preprocedural anxiety, hyperalgesia, and avoidance of healthcare, resulting in increased morbidity and mortality.⁸ Current evidence strongly supports the consistent use of four bundled modalities for elective needle procedures to reduce or eliminate pain experienced by children.^8,21 Although use in clinical practice may present challenges, the four bundle elements have been successfully implemented as the standard of care for needle procedures system-wide in children’s hospitals and pediatricians’ offices on several continents.^8,21 Bundle elements include

• Topical anesthesia “Numb the skin” for term infants 36 weeks of gestation and older, for example, 4% lidocaine cream (administered at least 30 minutes prior procedure), EMLA (lidocaine 2.5% and prilocaine 2.5%) cream (60 minutes prior), amethocaine [tetracaine] 4% gel (30–60 minutes prior) or needle-free lidocaine application via a sterile, single-use, disposable injector (J-tip).^22,23,24

• Sucrose or breastfeeding for infants 0–12 months.^25,26,27

• Comfort positioning provides a choice and encourages parents to hold children on their laps or be nearby.

◦ For infants, facilitate skin-to-skin, warmth, swaddling, or facilitated tucking.^{28,29,30,31,32,33,34,35}

◦ For children 6 months and older, upright is best.

◦ Children should never be held down as restraining children for procedures is never supportive, creates a negative experience, and increases resistance, anxiety, and pain.³⁶

• Distraction appropriate for age and developmental level, such as toys, stories, books, music, bubbles or pinwheels, stress balls, and apps, videos, or games on electronic devices.^37,38,39

These four simple modalities (or three to children older than 12 months) and not just some of them should be offered for all needle procedures for all children.^20,21

Plan B. For children who have already had suboptimal needle procedure experiences and anxiety and fear preclude them from being successful with the listed four strategies, consider referrals to psychology or child life for a coping plan and/or the use of minimal sedation, such as nitrous gas, to help them be successful and avoid retraumatization.^40,41,42

Note that all procedures, including needle procedures, should be carefully considered for children in PPC, especially at end of life, to evaluate the potential benefits and burdens, importance to the overall treatment plan, and the alignment with the established goals of care.

Considerations for Treating Pain in Children with Serious Illness

This chapter suggests a 12-step approach for advanced analgesia consideration in neonates, children, and adolescents with serious illness, based on the Education in Palliative and End-of-Life Care (EPEC)-Pediatrics curriculum.¹¹ The appropriate treatment choices depend on the clinical scenario and the context of the individual child and his or her family (including cancer vs. nonmalignant disease, infant vs. older child, verbal vs. nonverbal child, underlying pain pathophysiology, and goals of care). See Figure 23.2 for step-by-step considerations for advanced pain treatment in children with serious illness.

Step 1: Evaluation

As of July 2020, the internationally accepted International Association for the Study Pain (IASP) definition⁴³ of pain is “An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” and is expanded upon by the following six key points:

• Pain is always a personal experience that is influenced to varying degrees by biological, psychological, and social factors.

• Pain and nociception are different phenomena. Pain cannot be inferred solely from activity in sensory neurons.

• Through their life experiences, individuals learn the concept of pain.

• A person’s report of an experience as pain should be respected.

• Although pain usually serves an adaptive role, it may have adverse effects on function and social and psychological well-being.

• Verbal description is only one of several behaviors to express pain; inability to communicate does not negate the possibility that a human or a non-human animal experiences pain.

To successfully treat pain in a pediatric patient with serious illness it is paramount to take a detailed history, including medication history, and perform a comprehensive clinical exam. Based on the outcome of these evaluations, medical tests may be ordered if they might guide further treatment options. Most children with serious illnesses experience different distinct and at times overlapping entities of pain pathophysiologies concurrently and/or subsequently, thus explaining the need of protocols providing multimodal analgesia (Figure 23.3).⁸ These pain pathophysiologies include

• Acute somatic pain arises from the activation of nociceptors (peripheral nerve endings) caused by tissue injury that transmits noxious stimulation. Examples include chemotherapy-induced mucositis, open wounds, occult fractures, hip dysplasia, corneal abrasions, dental abscesses.

• Total pain: Cicely Saunders in the 1960s saw a broader view than the IASP definition, acknowledging the impact of spiritual and psychosocial aspects on the pain experience, coining the term “total pain,” which includes suffering that encompasses all of a child’s physical, psychological, social, spiritual, and practical struggles.⁴⁴ This is particularly true for children with palliative care needs, for whom the onset of pain may represent the relentless progression of a life-limiting or life-threatening disease.⁴⁵ For a more detailed review of the subject, please refer to the excellent article by Warlow and Hain.⁴⁵

• Neuropathic pain results from injury to or dysfunction of the somatosensory system. Examples include chemotherapy-induced neuropathy, phantom limb pain, or neurodegenerative disorders. Central pain is caused by a lesion or disease within the central somatosensory nervous system.

• Visceral pain results from the activation of nociceptors of the thoracic, pelvic, or abdominal viscera. Examples include bladder spasms, pancreatitis, or intrahepatic tumors.

• Chronic pain is usually described as pain beyond expected time of healing. Examples include functional abdominal pain, primary headaches, medication overuse headaches, and widespread musculoskeletal pain. A significant subset of children with serious illness also experience chronic pain in addition to their acute, neuropathic, visceral, and total pain. Of note, 20% of children develop chronic postsurgical pain (CPSP) after major surgery.⁴⁶

Step 2: Treat Underlying Causes

When a child with serious illness presents with a distressing symptom such as unrelieved pain, and this is concurrent with all other areas in pediatrics, it is key to identify and treat the underlying disease process as long as this is feasible and within the goals of care for the individual child and family. The aim is to identify and appropriately address comorbidities which may contribute to the pain experience, such as feeding intolerance, visceral hyperalgesia, fluid overload, constipation, spasticity/contractures, nausea, vomiting, reflux, untreated anxiety, depression or other mental health disorders, sleep disturbance, hypoactive/hyperactive delirium, medication withdrawal, and/or a seizure disorder. A sudden paralysis of the legs, possibly coinciding with loss of bladder and stool control may be indicative of tumor growth within the spinal canal and then might constitute a palliative emergency. This might be addressed with glucocorticosteroids such as dexamethasone, radiation, and/or neurosurgery, increasing the chance for the pediatric patient to return to improved or even normal functioning for a period.

In infants and neonates, these modalities include breastfeeding, non-nutritive sucking with sucrose 24%, and skin-to-skin contact.^25,26,47,48 In toddlers, school children, and young adults, age-appropriate effective integrative modalities for include aromatherapy, distraction, abdominal breathing, progressive muscle relaxation, biofeedback, hypnosis, yoga, acupressure, acupuncture, transcutaneous electrical nerve stimulation (TENS), Reiki, music, and massage.^{37,49,50,51,52,53,54,55,56,57,58,59,60} Many of these active mind-body techniques may be effective by decreasing pain, distressing symptoms and anxiety through involvement of several mechanisms simultaneously within the analgesic neuraxis.^{58,61,62,63,64}

Mind-body techniques such as distraction and guided imagery, which can be taught to the child and/or caregivers appear to modulate the release of endogenous opioids from the periaqueductal and periventricular gray regions to disinhibit descending inhibitory pathways of the brainstem to modulate pain at the supraspinal level.^{65,66,67,68,69,70,71}

Step 4: Social Work, Psychology, Chaplaincy, and Child Life

As described elsewhere in this book, advanced specialist PPC can only be provided by an interdisciplinary clinical care team; a lone physician or a sole nurse practitioner is not empowered nor able to provide comprehensive excellent pain assessment and treatment for children with serious advanced illness.

Physical therapy is advocated in the literature as an adjunctive modality with favorable outcomes in the prevention and treatment of pain in children with medical complexity.⁷² The physical therapist is the movement specialist on the interprofessional PPC team. Given the inextricable link between pain and movement, the physical therapist is optimally positioned to offer movement as analgesia in a preventative, restorative, supportive, or palliative context in accordance with the individual needs of a child and their family.⁷³

Conventional physical therapy may consist of activity modification, exercises to improve range of motion and strength, and the application of passive electrotherapeutic modalities such as transcutaneous electrical nerve stimulation (TENS), interferential current (IFC), or thermal agents.⁷³ However, contemporary thinking in physical therapy suggests an active movement-based approach that considers both cortical and peripheral intervention targets along a movement therapy continuum is preferred.^74,75

Malfliet et al. (2017) suggest that altered cortical processing may underpin the complex pain presentations in children with serious illness. Indeed, the recognition of the relationship of maladaptive cortical processing and pain suggests that a movement without moving approach, with the brain as the primary therapeutic target, be considered in physical therapy intervention. Perceptual manipulation using graded motor imagery, including implicit motor imagery, explicit motor imagery, and mirror visual feedback, permits novel stimulation of cortical regions associated with pain and movement thereby providing the child with pain-free brain-based movement which has been shown to reduce pain.⁷⁴ Furthermore, virtual and augmented reality may offer additional cortically based movement intervention that can be effective in modulating pain perception in both acute and complex pain presentations.⁷⁵

Brain-based movement interventions can be progressed to active foundational movement approaches, such as physical activity promotion, which are shown to decrease pain sensitivity via central inhibitory mechanisms.^76,77 Physical activity interventions yield optimal outcomes when tailored to the individual goals of the child and designed on a foundation of pain neuroscience education that targets maladaptive pain cognitions and fear of movement.^75,76

Graded exposure to goal-directed physical activity can offer the child access to new and novel sensations, decrease the risk of negative mental health sequelae associated with medical complexity, and empower the child and their parents in the management of their condition.⁷⁸

Movement-based physical therapy offers a simple and cost-effective suite of therapeutic options that can improve interprofessional palliative care for children. Well-designed systematic evaluation of movement-based physical therapy approaches are needed to enable strong clinical recommendations in the prevention and treatment of pain in children with medical complexity.

Pain is not only a common symptom in children with serious illness, it is also among the most feared.^2,79,80,81 Fear is a central affective component of pain,⁸² and rarely is this fear greater than when pain is experienced in the context of a life-threatening illness. Fears of disease progression and death also contribute to the experience of pain and can increase suffering in children with serious illness. Psychological interventions can be used, among many things, to address the fear and distress that pain and illness cause the child and their family, in turn impacting both pain management as well as the child’s emotional and sensory experience of pain. Psychotherapeutic interventions are particularly useful to address comorbid mental health issues^83,84,85 and suicidality⁸⁶ that can arise as a result of living with persistent pain and illness. Interestingly, while research in pediatric populations often falls behind that of adults, the recommendation to integrate psychological and psychiatric interventions into pain management has been especially embraced in pediatric populations.⁸⁷

Numerous approaches fit within the boundaries of psychological and psychiatric interventions for PPC, which are often used in combination. This includes guided imagery and breathing, psychoeducation, hypnosis, distraction, progressive muscle relaxation, biofeedback, and cognitive restructuring. Distraction is the most supported approach in children with serious illness, although it has been mostly studied within the context of cancer-related procedural pain and less well in other illnesses. Nonetheless, it is easily employed in broad procedural settings and can work well across a variety of ages and temperaments.⁸⁸ Several systematic reviews^89,90,91,92 show large effect sizes for distraction as an intervention for procedural pain in children, including several recent studies that support virtual reality–based distraction approaches.⁹³

Cognitive strategies, such as restructuring, are better studied in adult populations but are also commonly used with youth. These techniques are particularly important to address how the young patient interprets and makes sense of their pain. For example, a child with cancer may interpret pain as indicating a progression of their disease, fueling further distress.^94,95 Through cognitive restructuring, the child is encouraged to consider alternative, less-threatening interpretations, for example that the pain is a result of treatment targeting the disease. This, in turn, may reduce the distress caused by the pain as well as the perceived need for pharmacologic pain control. Importantly, the goals of cognitive restructuring can change over the course of the child’s disease—at later stages the focus may be on challenging different cognitions, such as “there is nothing I can do to control my pain.” The most appropriate strategy will also shift according to the course of disease and the child’s age—breathing techniques and distraction will be more appropriate for younger children and those with cognitive limitations due to more advanced disease.

As multiple psychological factors contribute to the child’s pain experience, multiple actors are also involved in its treatment. Parents play a critical role in shaping the child’s response to and management of pain^91,96,97,98 and are thus commonly integrated into intervention. The child’s attitudes and behavioral responses toward pain are often learned by observing and modeling the parent.⁹⁹ Thus, the parent’s own interpretations of the child’s pain could also be usefully addressed through cognitive restructuring. The parent also directly influences the management of the child’s pain in their interaction with the healthcare system, for example by communicating increases in the child’s pain to the medical team. One salient challenge faced by parents is managing empathic distress as a result of seeing their child in pain.^100,101 Psychological practitioners can work with parents on coping strategies to help them manage their distress, thus reducing the distress observed by the child and enabling more adaptive empathic care.¹⁰²

In addition to mental health professionals, other members of the child’s clinical team also influence the child’s pain experience via psychological mechanisms. Innovative research, again largely in adults, has revealed that a good therapeutic relationship can enhance placebo analgesia and thus reduce pain through psychological mechanisms (e.g., by reducing expectations of pain) and physiological pathways (e.g., by engaging the endogenous opioid system).¹⁰³ Psychological factors are also important in the effective delivery of pharmacological treatments, particularly when considered in a developmental context. For example, a teenager receiving morphine to control disease-related pain may feel uncomfortable reporting the side effect of constipation-related pain to a treating physician. Without being sensitive to these developmental considerations, the child’s overall pain experience will be poorly managed regardless of the availability of effective analgesics.

Psychological and psychiatric interventions are a vital part of our toolkit for effective pain management in PPC and are a cornerstone of shifting from a disease-centered to a child- and family-centered model of care. As precision in pharmacological treatment of pain grows, we need equal precision in the assessment and treatment of psychological factors that are integral to the child’s pain experience.

Chaplaincy

Chaplaincy provides spiritual care and supports to enhance coping in times of crisis, stress, or illness. Spirituality, religion, or life philosophy play an important role in the lives of most verbal patients receiving PPC, as well as their families. A link between spiritual coping and quality of life in adolescents with serious illness has been described.¹⁰⁴ Spirituality screening tools, such as the Faiths or Beliefs, Importance or Influence, Community, Address these issues (FICA) have been successfully implemented into clinical PPC¹⁰⁵ and should be considered part of a comprehensive pain assessment.

Child Life

Basic (or simple) analgesics include acetaminophen (paracetamol), nonsteroidal anti-inflammatory drugs (NSAIDs), and cyclooxygenase-2 (COX-2) inhibitors. In some countries dipyrone (metamizole) is included as a basic analgesia.¹⁰⁶ See Tables 23.1 and Table 23.6 for recommended dosing.

Due to the antipyretic property of all basic analgesics, in neutropenic and/or immunocompromised patients, these medications may suppress fever as an early sign of sepsis and as such should only be administered in close collaboration with the primary team (e.g., oncologist, transplant clinician)

“By the clock” dosing. When pain is constantly present, administration of both basic analgesia and an opioid should usually be scheduled “around-the clock” (e.g., acetaminophen every 6 hours scheduled and morphine every 4 hours scheduled). As-needed prescriptions only (without scheduled analgesia) often do not reach the patient, and “PRN” (“pro re nate” or “as-needed”) is often translated into “patient receives nothing,” with 69% of hospitalized pediatric patients for whom analgesics had been ordered not receiving a single dose in one study.¹⁰⁷

Acetaminophen (Paracetamol)

Acetaminophen is generally well-tolerated in pediatrics and lacks gastrointestinal and hematological side effects. The mechanisms of antinociception of this commonly administered analgesic remain unclear and seem to include the stimulation of descending (inhibiting) serotonergic pathways, which are possibly endocannabinoid-dependent, through COX-2 inhibition, nitric oxide (NO) synthesis blockade, and interaction with supraspinal calcium (Ca(v)3.2) channels.^108,109 Significant hepatoxicity¹¹⁰ is rare with standard dosing, but careful attention to dosing is paramount to avoid toxicity. The liver enzymes aminotransferase (AST) and alanine aminotransferase (ALT) and gamma-glutamyl transferase can increase with normal doses of acetaminophen; although those changes are probably unimportant in the absence of functional or synthetic liver impairment.^111,112 Acetaminophen appears to be opioid-sparing and works synergistically with opioids at normal opioid starting doses, but with high-dose opioids does not seem to add benefit.¹¹³ Intravenous (IV) acetaminophen does not offer a benefit over enteral administration and should only be considered when enteral or rectal administration is not feasible. In the United States, after a recent price rise of 240% ($40 for 1,000 mg), the cost of IV acetaminophen is artificially inflated when compared to the enteral forms.¹¹⁴

Nonsteroidal Anti-Inflammatory Drugs

NSAIDs, such as ibuprofen, naproxen, ketorolac, and meloxicam display an equianalgesic effect; in other words, in principle, one NSAID doesn’t provide better analgesia than another. Due to differences in pharmacokinetics, pharmacodynamics, and pharmacogenetics, there are of course interindividual variabilities. Ibuprofen is usually preferred because it carries the least gastrointestinal side effects among NSAIDs that are nonselective for COX-2.

NSAIDs should be used with caution in individuals with renal impairment and in patients with a history or risk of bleeding, including risk of gastrointestinal bleeding or ulcers, as this group of medication inhibits platelet aggregation. Ketorolac has the advantage of IV administration, but, due to higher risks of side effects in children, should be rotated to oral ibuprofen as soon as tolerated.

Compared to standard ibuprofen, the salt formulation (ibuprofen sodium), which is available over the counter in the United States and other countries, has a faster analgesic onset (within 10 minutes), only requires 50% of the dose, and has a longer duration of action.¹¹⁵

COX-2 Inhibitor

Celecoxib (a COX-2 much more than a COX-1 inhibitor) is commonly used in children with serious illness when classical NSAIDs are contraindicated (e.g., due to increased bleeding risks or gastrointestinal side effects). Celecoxib can be compounded into a liquid, thus easing administration in children, and a short course of COX-2 inhibitors can be safely used even in individuals who are undergoing surgery.¹¹⁶ It is yet unclear whether COX-2 inhibitors display a better cardiovascular risk profile or less renal toxicity compared to classic NSAIDs, as suggested by single studies.^117,118

Dipyrone

Dipyrone (metamizole) has an analgesic, spasmolytic, and antipyretic effects and is used to treat pediatric pain in many parts of the world.¹⁰⁶ Due to a possible risk of agranulocytosis with the use of this medication, it has been banned in the United States and several other countries. The analgesic efficacy of IV dipyrone appears similar to that of IV acetaminophen (paracetamol).¹⁰⁶ There is no evidence to support that dipyrone is equivalent or even superior to NSAIDs in pediatric pain.¹⁰⁶

Opioids

Opioids are indicated in children with serious illness for both medium to severe acute pain due to tissue injury as well as in the treatment of dyspnea. Morphine remains the “gold standard,” but other “strong” opioids, such as fentanyl, oxycodone, hydromorphone, diamorphine (in the UK only), and methadone are equally effective in their respective analgesic effects.

Opioid-associated side effects (e.g., constipation, pruritus, and nausea) should be anticipated and treated accordingly. For pediatric opioid starting doses, see Table 23.3; for usual patient-controlled-analgesia (PCA) pump starting doses see Table 23.4.

Opioid rotation may be necessary if tolerance develops or dose-limiting opioid toxicity occurs. A switch from one opioid to another is often accompanied by a change in the balance between analgesia and side effects.¹³⁴ A favorable change in opioid side-effect profile may be experienced if there is less cross-tolerance at the opioid receptors mediating analgesia than at those mediating adverse effects. If rotating opioids because of decreasing effectiveness or limiting side effects (i.e., because of incomplete cross-tolerance), the clinician can consider starting at around 50% of the equianalgesic dose and titrating to effect. However, the required decrease for incomplete cross-tolerance may be higher or lower, depending on the clinical context of the individual patient.¹³⁵

“By the clock” dosing. When pain is constantly present, administration of basic both analgesia and opioid should usually be scheduled “around-the-clock” (e.g., acetaminophen every 6 hours scheduled and morphine every 4 hours scheduled).¹⁰⁷

“Weak” Opioids

“Weak” opioids display an analgesic ceiling effect; in other words, an increase in dose does not result in increased analgesia beyond a certain dose. This group includes mixed agonist/antagonist, partial opioid agonists, and multimechanism analgesics. With the explicit exception of tramadol, and possibly buprenorphine, this group of opioids can not usually be recommended in PPC.

Mixed agonist/antagonist (such as nalbuphine and butorphanol) agents can precipitate withdrawal symptoms when used in opioid-tolerant patients. Tapentadol, a mu (delta, kappa)-receptor agonist and a norepinephrine reuptake inhibitor is a close chemical and structural relative of tramadol and so far, it is unclear whether it has any advantage over tramadol.¹³⁶ The high price and no current pediatric data make it an unlikely choice due to inexpensive, safe, and efficacious alternatives.

Codeine

Codeine can no longer be recommended due to pediatric deaths, especially in cytochrome P450 2D6 ultra-rapid metabolizers, and it has become obsolete.^{137,138,139,140,141,142,143} Of note, in low-income countries where morphine might not be available, the use of codeine may be supported if no other strong opioids are available.

Codeine’s ability to provide effective analgesia through its active metabolite, morphine, via the cytochrome P450 2D6 (CYP2D6) system is limited in both “poor” as well as “intermediate” metabolizers (more than one-third of patients). Commonly observed side effects of codeine include nausea, vomiting, constipation, pruritus, and urinary retention. Clinical experience suggests that codeine causes more nausea and vomiting than any other standard analgesic in children.¹⁴⁴

Hydrocodone

Hydrocodone (dihydrocodeinone) is usually not available outside the United States, but in the United States is by far the single most commonly prescribed opioid. Like codeine, it appears that hydrocodone is an inactive pro-drug, and the main analgesic effect results from the metabolite hydromorphone.¹⁴⁵ CYP2D6 ultra-rapid metabolizer (similar to codeine’s metabolism into morphine) have a much higher risk of respiratory depression, and pediatric death have occurred.^146,147 As such, hydrocodone (analogue to codeine) cannot be recommended for use in pediatrics.

Tramadol

Tramadol, a multimechanistic analgesic, on the other hand, continues to play a key role not only in outpatient surgery (e.g., more than 6,000 pediatric tramadol scripts were filled at Children’s Minnesota in 2018 in part due to its relative safe respiratory profile), but also in treating episodes of inconsolability in children with progressive neurologic, metabolic, or chromosomally based conditions with impairment of the CNS. Surprisingly, and not well based on scientific evidence, the US Food and Drug Administration (FDA) issued a warning against pediatric use of tramadol and cited the data of three children who have died worldwide in the previous 49 years, therefore actually making it far safer than any other opioid. Unfortunately, this warning may place children at greater risk for unrelieved pain and other distressing symptoms by encouraging clinicians to either use strong opioids in the outpatient setting with a higher risk of respiratory depression or not using opioids at all.¹⁴⁸

Tramadol is a multimechanistic analgesic commonly used worldwide for pediatric pain management and palliative care.^{149,150,151,152} Studies examining efficacy and safety of this medication have been conducted worldwide, and results support its use in children.^{141,153,154,155,156,157,158,159,160,161,162,163} The analgesic potency of tramadol falls somewhere between ibuprofen and morphine.¹⁶⁴ Although only commercially available in tablet form in the United States, an oral suspension may be compounded into a stable and inexpensive liquid.¹⁶⁵ Outside the United States, both IV and liquid tramadol are readily available. Although tramadol is metabolized into the more potent O-desmethyltramadol, tramadol (unlike codeine) itself appears to be a potent analgesic.

For poor CYP2D6 metabolizers, the parent compound tramadol remains active; hence, those individuals experience no decrease or only a slightly diminished analgesic effect, possibly supported by parallel CYP3A4 metabolism.¹⁶⁴ Data suggest that tramadol administration may result in fewer side effects than with full mu-opioid agonists,¹⁶⁶ and tramadol appears far safer than codeine when it comes to risk of respiratory depression. One study examining statewide poison control center data in the United States¹⁶⁷ reported no respiratory depression in children younger than 6 years who ingested 10/mg/kg or less (up to 5–10 times the recommended dose); however, 2 out of 87 (2%) adults in the sample did experience respiratory depression.

Notably, tramadol has been shown to be particularly helpful in treating neuropathic pain and visceral hyperalgesia⁷ presenting as episodes of inconsolability in children with neurologic, metabolic, or chromosomally based condition with impairment of the CNS, such as mitochondropathies.

Team Reflection

This opioid displays a somewhat unique pharmacology compared to other agents in its class. As a partial mu-opioid receptor agonist with long duration of action, it can cause an “opioid blockade.” It is also a delta-opioid receptor antagonist and a kappa-opioid (partial agonist) receptor antagonist (i.e., possibly less likely to cause psychomimetic effects such as dysphoria/hallucinations). The main liver metabolite norbuprenorphine, however, is a partial kappa-agonist and a full mu- and delta-opioid receptor agonist, and as such might be antagonized by buprenorphine.^168,169 In the United States, transdermal patches are available at comparatively low doses only—5, 10, and 20 mcg/hr—whereas in most other countries (e.g., the United Kingdom), patches are available that release 35, 52.5 and 70 mcg/hr buprenorphine. In practice, buprenorphine might be useful in children with mild to moderate pain with nonmalignant life-limiting conditions, especially when there is concern of opioid-induced constipation.

“Strong” Opioids

This group are full mu-opioid receptor agonists, with methadone representing additionally a multimechanistic analgesic. Morphine, fentanyl, oxycodone, hydromorphone (in the UK only: diamorphine), and methadone are very effective in providing analgesia (and treatment of dyspnea at end of life) at equianalgesic doses (see Tables 23.3, 23.4, and 23.6 for starting doses). One opioid per se is not necessarily “more effective” or “stronger” than another. In fact, at equianalgesic doses, all strong opioids are expected to be equally effective in reducing pain. Having said this, in pediatric patients with serious illness, an opioid rotation is indicated in up to 40% of the cases when tolerance develops or dose-limiting opioid side effects occur (e.g., unrelieved pain with respiratory depression and/or nausea).¹³⁵ A switch from one opioid to another is often accompanied by a change in the balance between analgesia and side effects,¹³⁴ taking advantage of incomplete cross-tolerance.

Opioid-associated side effects, especially constipation, but also pruritus, nausea, and urinary retention should be anticipated and treated accordingly. In the scenario of severe adverse effects, such as opioid-induced respiratory depression, treatment options include reducing (or briefly pausing) the opioid dose (in case of adequate analgesia) or rotating the opioid (if inadequate analgesia) at equianalgesic doses, minus a decrease for incomplete cross-tolerance. That reduction often is around 50%; however, in individual case it may be much higher or lower.¹³⁵

The choice of an opioid is often simply dictated by availability (many low- to medium-income countries have limited or no access to opioids in general), but also sometimes by cognitive bias by clinicians, institutional leadership, and regulators.

Morphine

Morphine is considered the gold standard for analgesia against which all other opioids are compared. Routes of administration include oral, sublingual, IV, intramuscular, subcutaneous, intrathecal, and epidural. Morphine is also effective topically in open wounds.¹⁷⁰ See Tables 23.3, 23.4, and 23.6 for typical starting doses, which must be titrated to effect.

Morphine is metabolized by liver glucuronyl-transferase into “the good guy” morphine-6 glucuronide (M6G) and “the bad guy” morphine-3 glucuronide (M3G). M6G is a much stronger analgesic (40–100 times stronger) and displays adverse effects including nausea, vomiting, sedation, and respiratory depression. M3G is not an analgesic but is a mu-opioid antidote with unique adverse effects, especially hyperexcitability and neurotoxicity. The ratio of M6G/M3G thereby defines the analgesia-to-adverse effect profile in individual children. Both metabolites need to be excreted by the kidney, and children in renal failure have a higher risk of unwanted side effects. Fentanyl or methadone, neither of which is excreted renally, is likely to be a better choice in this scenario.

In standard practice, morphine is most commonly administered via the oral or IV routes. Following oral dosing, morphine has a significant first-pass metabolism in the liver. The currently accepted oral-to- IV potency ratio for morphine is 1:3.¹⁷¹ Therefore, the usual practice when converting oral morphine to IV is to divide the oral dose by 3 (i.e., 3 mg oral morphine equals 1 mg IV morphine). Morphine is available orally as a concentrated solution, immediate-release tablets, and sustained-release tablets and sachets (the latter not available in the United States).

Renal impairment. M3G does not possess analgesic properties, but is instead nociceptive, does not bind to opioid receptors, and may be responsible for some of the adverse CNS effects such as myoclonus. M3G and M6G are excreted by the kidneys, and their elimination is directly related to creatinine clearance. In patients with renal compromise, M3G and M6G may accumulate in the blood and cerebrospinal fluid, leading to unwanted toxicity (M6G may cause oversedation, pruritus, nausea, etc.; M3G may cause increased nociception, hyperexcitability). Morphine should therefore be administered with caution to patients with renal impairment.

Liver impairment. Only with severe liver failure (e.g., as shown by increased prothrombin time) does morphine’s half-life substantially increase, making opioid induced-side effects are more likely.

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