Neuropathic Pain Management in Pediatrics

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PATIENT CASE

KP is a 4-year-old girl with a primary diagnosis of multi-organ failure with secondary of sickle cell disease and history of hand-foot syndrome at 9 months of age. She weighs 12.2 kg (27 pounds) and has no known drug allergies. KP is receiving hospice care at home where she lives with her parents and older brother.

Medications:

  • Morphine 20mg/ml oral liquid; 0.5ml (10mg) PO every 4 hours while awake for pain and 0.25ml (5mg) every 2 hours as needed for breakthrough pain
  • Ibuprofen 100mg/mL suspension: 1.5ml (150mg) PO every 8 hours for pain
  • Senna liquid; 2.5ml PO at bedtime for constipation
  • Ondansetron 4mg/5ml oral liquid; 2.5ml (2mg) PO every 8 hours to prevent nausea/vomiting

KP has experienced pain in her abdomen, bones, joints and soft tissue, which is common for sickle cell disease. Her pain is typically managed with scheduled morphine and ibuprofen. More recently, KB is describing a constant, burning pain in her legs that has not responded to breakthrough morphine. KP rates the pain as 8 on the FACES Pain Scale Revised 1 and is averaging 50mg of morphine per day. Her mother is a nurse and familiar with methadone and its use for different types of pain. Her parents prefer not to add medications, stating that it is already difficult to give the 4 medications currently prescribed.

CONDITIONS PRODUCING NEUROPATHIC PAIN IN CHILDREN

Neuropathic pain results from damage to nerve fibers (pressure, trauma, swelling, inflammation). Pain is described as burning, shooting, and stinging and can be associated with skin color changes or an inability to tolerate even light touch without experiencing pain. 2

Although many of the neuropathic pain syndromes seen in adults are not diagnosed as frequently in children, children may experience neuropathic pain from migraine headaches, surgery scars, phantom limb pain following amputation, tumors, autoimmune and degenerative neuropathies, such as Charcot-Marie-Tooth disease or Guillain-Barre´ syndrome, and complex regional pain syndromes. Neuropathic pain is also common in pediatric patients with cancer. 3,4

Other diseases that are diagnosed during childhood known to cause neuropathic pain include erythromelalgia, toxic and metabolic neuropathies, mitochondrial disorders, paroxysmal extreme pain disorder, and Fabry disease. There is also evidence supporting a significant presence of neuropathic pain in sickle cell disease. 3,4

ASSESSMENT

Despite the number of pediatric conditions identified with a neuropathic pain component, there are no screening or assessment tools specific for assessing neuropathic pain in pediatric patients except for chemotherapy-induced peripheral neuropathy (CIPN). 6 Given this, providers must rely on standard pain management assessment tools, such as those validated in adult populations, and account for age-related limitations. 4

MANAGEMENT

Nonpharmacological therapies include: 6

  • Developmental interventions: Involve the patient in decision-making where appropriate and provide honest, developmentally appropriate information
  • Physical interventions: Positioning, judicious use of temperature changes, healing touch, and acupressure
  • Sensory interventions: Art therapy, music therapy and aromatherapy
  • Psychology-based interventions: Verbal distraction through conversation, breathing exercises, visual distractions such as lava lamps and computer games

The most common medication used for neuropathic pain is gabapentin (Neurontin®). Other medications to consider including tricyclic antidepressants (TCAs) in patients with concomitant depression, and anticonvulsants. Most opioids have no role in the treatment of neuropathic pain.Methadone, however, has actions on both opioid and N-methyl-D-aspartate (NMDA) receptors making it useful for patients with mixed nociceptive and neuropathic pain.

PEDIATRIC DOSING

Methadone

  • For mixed nociceptive and neuropathic pain
  • 0.1mg/kg/dose PO every 8 hours 6
  • OR 0.1-0.2mg/kg/dose every 4 hours for the first 2-3 doses, then every 6-12 hours (max: 5mg/dose initially) 3
  • Common adverse reactions include dizziness, drowsiness, QT prolongation
  • Caution recommended in patients with cardiac disease, especially arrhythmias
  • Many drug interactions

Gabapentin (Neurontin®) 2,3,6,7

  • First line for neuropathic pain
  • Initial dose 3-5mg/kg/dose (max: 300mg/dose initially)
  • Day 1, give 1 dose; Day 2, give 2 doses; then Day 3 & onward, give 3 doses
  • Common adverse reactions include dizziness, drowsiness, fatigue and headache

Amitriptyline (Elavil®) 6,7

  • For neuropathic pain with concomitant depression in children older than age 6
  • 0.1mg/kg/day in single (typically given at bedtime) or divided doses (max: 5mg/kg/day)
  • Common adverse reactions include dizziness, drowsiness, constipation, blurry vision, dry mouth
  • Caution recommended in patients with cardiac disease and sensitive to anticholinergic effects

Nortriptyline (Pamelor®) 6,7

  • Indicated for neuropathic pain with concomitant depression in children older than age 6
  • 0.05mg/kg/day in divided doses (max: 10-20mg/day for child; 30-50mg/day for adolescent)
  • Common adverse reactions include dizziness, drowsiness, constipation, blurry vision and dry mouth
  • Caution recommended in patients with cardiac disease and sensitive to anticholinergic effects

Carbamazepine (Tegretol®) 6,7

  • For refractory neuropathic pain
  • Age < 6 years: 10-20mg/kg/day in divided doses BID for solid dosage forms (suspension given Q.I.D.) • Age 6-12 years: 100mg ER BID or 50mg IR tab or suspension Q.I.D. (max: Age 6-15y is 1000mg/day; Age > 15y is 1200mg/day)
  • Common adverse reactions include ataxia, constipation, drowsiness, nausea and vomiting
  • Many drug interactions; requires therapeutic serum levels

Mexiletine (Mexitil®) 6,7

  • For refractory neuropathic pain
  • 1.4mg/kg/dose TID (max: 900mg/day)
  • Increase by 1mg/kg every 2-3 days as tolerated
  • Common adverse reactions include ataxia, dizziness, nausea, vomiting, heartburn, and tremor
  • Mexiletine is an antiarrhythmic agent; caution recommended in patients with cardiac disease, renal impairment and seizure disorders

ASSESSMENT:

KP is thought to be experiencing neuropathic pain based upon its description as “burning”, lack of response to morphine and ibuprofen, and her history of sickle cell disease. KP has no history of depression and has not yet trialed an adjuvant agent for neuropathic pain. KP’s parents prefer not to add to her pain management regimen, but rather to replace one agent for another, if possible.

RECOMMENDATIONS

Consider replacing morphine scheduled doses with methadone by evaluating the benefits versus the risks of this therapy. With regularly scheduled use, methadone has a long-acting duration with effects on both opioid and NMDA receptors, making it beneficial for somatic (inflammatory and bone pain and muscle aches), visceral (organ pain, referred pain) and neuropathic pain. It is also inexpensive and available in a concentrated liquid, making it feasible for children unable to swallow solid dosage forms. Methadone interacts with most antiemetic medications, including the ondansetron that KP takes on a scheduled basis. Both medications increase the risk of QT prolongation separately, most commonly at higher doses, however the reaction may occur at any time. Although routine cardiac monitoring via EKG is not common in hospice, KP should be monitored for other signs of QT prolongation such as fainting and seizures.

Initiating methadone therapy:

  • Discontinue scheduled morphine liquid
  • Continue the “as needed” morphine liquid regimen at “0.25ml (5mg) every 2 hours as needed”
  • Using a 4:1 morphine:methadone conversion ratio, convert 50mg morphine/day into oral methadone equivalent/day 8,9
  • Begin methadone 10mg/ml solution; 0.25ml (2.5mg) PO every 8 hours
  • Encourage the use of “as needed” morphine, especially during the first 7 days of methadone use
  • On day 5-7, assess use of breakthrough morphine and adjust methadone regimen accordingly

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FOR ADDITIONAL INFORMATION ON THIS TOPIC, PLEASE REVIEW THE BELOW REFERENCES:

References:
1. Hicks CL, von Baeyer CL, Spafford P, et al. The Faces Pain Scale-Revised: Toward a common metric in pediatric pain measurement. Pain. 2001;93:173-183. Site link
2. Komatz K, Carter B. Pain and symptom management in pediatric palliative care. Pediatrics in Review. 2015 Dec;36(12):527-534. DOI: 10.1542/pir.36-12-527
3. Ferrell BR, ed. HPNA Palliative Nursing Manuals. Pediatric Palliative Care. New York: Oxford University Press;2016.
4. Morgan KJ, Anghelescu DL. A review of adult and pediatric neuropathic pain assessment tools. Clin J Pain. 2017 Sep;33(9):844-852. DOI: 10.1097/AJP.0000000000000476
5. Gilchrist L, Tanner L, Hooke M. Measuring chemotherapy-induced peripheral neuropathy in children: development of the Ped-mTNS and pilot study results. Rehabil Oncol. 2009;27:7–15.
6. Shega JW, Paniagua MA, eds. AAHPM. Essential Practices in Hospice and Palliative Medicine: UNIPAC 7: Pediatric Palliative Care and Hospice, 5th edition. Pain Management. Chicago: AAHPM;2017.
7. Clinical Pharmacology [database online]. Tampa, FL: Elsevier/Gold Standard, Inc.; 2019. Access 2019 Jan.
8. Shega JW, Paniagua MA, eds. AAHPM. Essential Practices in Hospice and Palliative Medicine: UNIPAC 3: Pain Assessment and Management, 5th edition. Pain Management. Chicago: AAHPM;2017.
9. McPherson ML. Demystifying Opioid Conversion Calculations: A Guide for Effective Dosing, 2nd edition. Bethesda; American Society of Health-System Pharmacists, Inc.:2018.

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