Stefan J. Friedrichsdorf, MD,

Transcription

1 Pain Treatment in Children with Serious Illness and Intellectual Disability: From Myths, Morphine and Multimodal Analgesia Stefan J. Friedrichsdorf, MD, FAAP Medical Director, Department of Pain Medicine, Palliative Care & Integrative Medicine Children's Hospitals and Clinics of Minnesota, Minneapolis/St. Paul, MN Associate Professor of Pediatrics, University of Minnesota Medical School Objectives Evaluate assumptions about opioid use in children Discuss how multiple agents, interventions, rehabilitation, psychological and integrative ( non-pharmacologic ) therapies act synergistically for more effective pediatric pain control with fewer side effects than a single analgesic or modality Practice formulating a treatment plan for a case-study in small

2 Causes of death in US children 2015 due to life-limiting conditions 0-24 years (n=11,933) Chronic Low. Respiratory Disease 7% Circulatory System Disease 4% Other 5% Heart Disease 11% Congenital Anomalies 50% Malignant Neoplasms 23% NaSonal Vital StaSsScs System, NaSonal Center for Health StaSsScs, CDC hups:// leading_causes_of_death_by_age_group_ 2015-a.pdf Distressing Symptoms = Common in PPC Wolfe J, Orellana L, Ullrich C et al Symptoms and Distress in Children with Advanced Cancer: Prospective Patient- Reported Outcomes from the PediQUEST Study, JCO Symptoms of PPC patients Symptom distress is strongly associated with health-related quality of life; Children with cancer: during the last 12 weeks of life, 11 distressing symptoms were associated with reductions in HRQOL Rosenberg AR, Orellana L, Ullrich C, Kang T, Geyer JR, Feudtner C, et al. Quality of Life in Children With Advanced Cancer: A Report From the PediQUEST Study. J Pain Symptom Manage. 2016;52(2): Feudtner C, Kang TI, Hexem KR, Friedrichsdorf SJ, Osenga K, Siden H, et al. Pediatric palliative care patients: a prospective multicenter cohort study. Pediatrics 2011;127(6):

3 Trigger Diagnoses for Consults UK: all PICU admissions over 15 months (n=89,127) Fraser LK, Parslow R. Children with life-limiting conditions in paediatric intensive care units: a national cohort, data linkage study. Arch Dis Child Children with life-limiting conditions (LLC) 57.6% (n=89,127) of PICU admissions 72.90% (n=4,821) of deaths Pediatric Cancer: presence of trigger diagnoses" increased likelihood of palliative principle introduction 3.41 times (p < 0.003) Weaver MS, Rosenberg AR, Tager J, Wichman CS, Wiener L. A Summary of Pediatric Palliative Care Team Structure and Services as Reported by Centers Caring for Children with Cancer. J Palliat Med. 2018;21(4): "If you can't add life to my son's days, then don't add days to my son's life" Father of a toddler to Dr. Sunny Anand on PICU Outcomes Improve with PPC Involvement Parents of children with cancer report less distress from pain, dyspnea and anxiety at EOL Wolfe et al. J Clin Onc 2008 Children who received PPC/Oncology more likely to have fun (70% versus 45%) and to experience events that added meaning to life (89% versus 63%) Friedrichsdorf SJ, Postier AC, Dreyfus J, Sencer S, Wolfe J: Improved Quality of Life in Children with Cancer at End of Life related to Home-based Palliative Care. J Pall Medicine (2): Families who received PPC/Oncology report improved communication Kassam A, Skiadaresis J, Alexander S et al Differences in End-of-Life Communication for Children with Advanced Cancer who were Referred to a Palliative Care Team. Pediatr Blood Cancer, (8): p Children receiving PPC experience shorter hospitalizations and fewer emergency department visits Ananth, P., et al., Hospital Use in the Last Year of Life for Children With Life- Threatening Complex Chronic Conditions. Pediatrics, (5): p

4 PPC = better clinical care? Integration of PPC inpatient team associated with fewer diagnostic / monitoring procedures and improved pain management documentation at end-of-life Osenga K, Postier A, Dreyfus J, Foster L, Teeple W, Friedrichsdorf SJ. A Comparison of Circumstances at the End of Life in a Hospital Setting for Children With Palliative Care Involvement Versus Those Without. J Pain Symptom Manage. 2016;52(5): Involvement of PPC team with adolescent and young adult oncology patients associated with the receipt of less intensive treatments Snaman JM, Kaye EC, Lu JJ, Sykes A, Baker JN. Palliative Care Involvement Is Associated with Less Intensive End-of-Life Care in Adolescent and Young Adult Oncology Patients. J Palliat Med. 2017;20(5): last month of life: on ventilator: 34% vs 63% invasive procedure 1 vs 3 fewer deaths in the ICU (38% vs 68%) DNR 2 days vs 6 days before death So, how do we treat the individual pain patient in front of us? Hmhh... Spoiler Alert: Crystal-clear answer on 3rd last slide! Alexis Lexi 7-year-old girl (20 kg) Progressive neurologic, metabolic or chromosomally based condition with impairment of the central nervous system (e.g. mitochondrial disease) Multiple long-term hospitalizations for complications of disease & therapy At home; intractable pain

5 Video Advanced management of pain in PPC: Step 1 (1) Identify and treat underlying disease process Lexi Assuming Patient has mixed pain What are the next steps?

6 What are we measuring...? (1) Nociceptive Pain: arises from the activation of peripheral nerve endings (nociceptors) that respond to noxious stimulation [e.g. localized, sharp, squeezing, stabbing, or throbbing] Somatic (for example, muscles, joints) Chronic somatic pain typically well localized & often results from degenerative processes (such as arthritis) (2) Visceral (internal organs) [poorly localized, dull, crampy, or achy] (3) Psycho-social-spiritualemotional Pain / Total Pain (4) Persistant (Chronic) Pain Pain beyond expected time of healing (5) Neuropathic Pain: resulting from injury to, or dysfunction of, the somatosensory system. [burning, shooting, electric, or tingling] Central pain: caused by a lesion or disease of the central somatosensory nervous system What are we measuring...? 10 Child A Child B Neuropathic Pain Visceral Pain 5 Somatic Pain My heart hurts Pain Score 9/10 0 Somatic Pain Validated Pinky Scale (PS) Pain Assessment

7 So how do clinicians do in pain assessment? Comprehensive Review Seers T, Derry S, Seers K, Moore RA. Professionals underestimate patients' pain: a comprehensive review. Pain. 2018;159(5): High-quality studies (blind, comprehensive, or random sampling, >200 patients) consistently reported underestimation (10/11; 91%) Extent of underestimation tended to increase with pain severity Professionals consistently tend to underestimate pain compared with assessment by patients This tendency is more pronounced with more severe pain, and the extent of underestimation can be large It is likely that this contributes to undertreatment of pain Measuring pain alone? High specificity, low sensitivity? Don t forget: Withdrawal: WAT-1 score Franck, L et al, (2008) Ped Crit Care Med, Vol 9, no. 6 familynursing.ucsf.edu/research-and-clinical-tools Neonatal Abstinence Scoring Tool (Finnegan) Finnegan LP. Neonatal abstinence. In: Nelson NM, ed. Current Therapy in Neonatal Perinatal Medicine. 2nd ed. Toronto, Ontario: BC Decker Inc; 1990 Delirium: CAPD Traube, C., et al., Cornell Assessment of Pediatric Delirium: a valid, rapid, observational tool for screening delirium in the PICU. Crit Care Med, (3): p Sedation: SBS score Curley, M.A., et al., State Behavioral Scale: a sedation assessment instrument for infants and young children supported on mechanical ventilation. Pediatr Crit Care Med, (2): p Is it Mixed Pain...? Children with CP: Daily pain 8.1% Houlihan CM, O Donnell M, Conaway M, Stevenson RD: Bodyli pain and health-related quality of life in children with cerebral palsy. Develop Med Child Neurol 2004, 46: Cognitively impaired, non-communicating children: Daily pain 23.5 % Stallard P, Williams L, Lenton S, Velleman R: Pain in cognitively impaired, non-communicating children. Arch Dis Child 2001; children with progressive, non-curable genetic, metabolic, or neurological conditions: Pain 53% [Most of the time: 21.8 %] Friedrichsdorf SJ, Postier AC, Andrews GS, Hamre KES, Steele R, Siden H: Pain reporting and analgesia management in 270 children with a progressive neurologic metabolic or chromosomally based condition with impairment of the central nervous system cross sectional, baseline results from an observational longitudinal study. J Pain Research 2017 (10): HOT OFF THE * PRESS *

8 Pain Chronic Pain Psychological pain Mental Health Anxiety Nociceptive Pain Deconditioned Neuropathic Pain Depression Social Pain Poor sleep hygiene School absenteeism Spiritual Pain Visceral Pain Racial Disparity Delirium Total Pain Withdrawal Multimodal Analgesia No Needless Pain: The Children s Comfort Promise Advanced management of pain in PPC: Step 2 (2) Integrative therapies & Rehabilitation: manage comorbidities (anxiety, sleep disturbances). Psychological Therapies. (1) Identify and treat underlying disease process (radiation?) (corticosteroids?)

9 Integrative, rehabilitative & supportive therapies Expected part of treatment protocol; Age-appropriate modalities include Physical (massage, TENS, comfort positioning, allowing family for close contact/touch) Rehabilitation (physical therapy, occupational therapy) Early increasing-intensity treadmill exercise reduces neuropathic pain (in rats) Lopez- Alvarez, V.M., et al., Early increasing-intensity treadmill exercise reduces neuropathic pain by preventing nociceptor collateral sprouting and disruption of chloride cotransporters homeostasis after peripheral nerve injury. Pain, (9): p Behavioral (deep breathing, imagery, hypnosis, smartphone/tablet apps ) Acupressure, acupuncture, aromatherapy Integrative modalities Integrative modalities effective in management of pediatric pain Hunt, K.; Ernst, E. The evidencebase for complementary medicine in children: A critical overview of systematic reviews. Arch Dis Child 2011, 96, ; Friedrichsdorf, S.; Kuttner, L.; Westendorp, K.; McCarty, R. Integrative pediatric palliative care. In Integrative pediatrics, Culbert, T.; Olness, K., Eds. Oxford University Press: pp ; Evans, S.; Tsao, J.C.; Zeltzer, L.K. Complementary and alternative medicine for acute procedural pain in children. Alternative therapies in health and medicine 2008, 14, include Hypnosis Kuttner, L.; Friedrichsdorf, S.J. Hypnosis and palliative care. In Therapeutic hypnosis with children and adolescents., 2nd ed.; Crown House Publishing Limited: Bethel, 2013; pp ; Richardson, J.; Smith, J.E.; McCall, G.; Pilkington, K. Hypnosis for procedure-related pain and distress in pediatric cancer patients: A systematic review of effectiveness and methodology related to hypnosis interventions. J Pain Symptom Manage 2006, 31, Guided imagery Dobson, C.E.; Byrne, M.W. Original research: Using guided imagery to manage pain in young children with sickle cell disease. The American journal of nursing 2014, 114, 26-36; test 37, 47. Yoga Bussing, A.; Ostermann, T.; Ludtke, R.; Michalsen, A. Effects of yoga interventions on pain and pain-associated disability: A metaanalysis. The journal of pain : official journal of the American Pain Society 2012, 13, 1-9.; Evans, S.; Moieni, M.; Taub, R.; Subramanian, S.K.; Tsao, J.C.; Sternlieb, B.; Zeltzer, L.K. Iyengar yoga for young adults with rheumatoid arthritis: Results from a mixed-methods pilot study. J Pain Symptom Manage 2010, 39, Acupuncture Vas, J.; Santos-Rey, K.; Navarro-Pablo, R.; Modesto, M.; Aguilar, I.; Campos, M.A.; Aguilar-Velasco, J.F.; Romero, M.; Parraga, P.; Hervas, V., et al. Acupuncture for fibromyalgia in primary care: A randomised controlled trial. Acupunct Med Massage Verkamp, E.K.; Flowers, S.R.; Lynch- Jordan, A.M.; Taylor, J.; Ting, T.V.; Kashikar-Zuck, S. A survey of conventional and complementary therapies used by youth with juvenile-onset fibromyalgia. Pain Manag Nurs 2013, 14, e Biofeedback Blume, H.K.; Brockman, L.N.; Breuner, C.C. Biofeedback therapy for pediatric headache: Factors associated with response. Headache 2012, 52, Integrative Pain & Symptom Management A Pediatrician s Top 10 Apps for Distraction & Pain Management NoNeedlessPain.org

10 Nociceptive Pathways & Primary Sites of Action of Analgesics Thalamus 2nd Neuron Aδ or C fiber Acetaminophen (Paracetamol) Injury NSAIDs Nociceptive Pathways & Primary Sites of Action of Analgesics Thalamus Periaqueductal grey (endorphins) Integrative (non-pharmacological) therapies Descending Inhibition + 2nd Neuron Descending pathways that modulate transmission of nociceptive signals originate in periaqueductal gray, locus coeruleus, anterior cingulate gyrus, amygdala & hypothalamus: are relayed through brainstem nuclei in the PEG and medulla to spinal cord. Inhibitory transmitters involved in these pathways incl. norepinephrine, 5-hydroxytryptamine, dopamine, & endogenous opioids. Opioids Aδ or C fiber Injury Acetaminophen (Paracetamol) NSAIDs

11 Nociceptive Pathways & Primary Sites of Action of Analgesics Thalamus CORTEX: -Stress - Anxiety - Catastrophizing - Depression - perceived injustice - disturbed Sleep ON OFF 2nd Neuron Periaqueductal grey (endorphins) Integrative (non-pharmacological) therapies Aδ or C fiber Opioids Acetaminophen (Paracetamol) Injury NSAIDs Advanced management of pain in PPC: Step 3 (3) Basic Analgesia plus Opioid (2) Integrative therapies & Rehabilitation: manage comorbidities (anxiety, sleep disturbances). Psychological Therapies. (1) Identify and treat underlying disease process (radiation?) (corticosteroids?) Multimodal (Opioid-sparing) Analgesia Basic Analgesics Acetaminophen / Paracetamol NSAIDs Integrative Therapies Such as: Massage Distraction Deep Breathing Biofeedback Aromatherapy Hypnosis Psychology CBT Rehabilitation Exercise, Physical Therapy Sleep Hygiene OT

12 WHO Principle: Using a Two-Step Strategy WHO Step 1 Mild Pain Ibuprofen and/or Acetaminophen (Paracetamol) Other NSAIDs? Cox-2 Inhibitor? Citius, Altius, Fortius...? Ibuprofen salts: fast-acting formulations Moore, R.A., et al., Faster, higher, stronger? Evidence for formulation and efficacy for ibuprofen in acute pain. Pain, (1): p Advil Film-Coated Tablets, contains 266 mg of ibuprofen sodium (equivalent to 200 mg of standard ibuprofen) Produced significantly better analgesia over 6h, fewer remedications than standard formulations 200-mg fast-acting ibuprofen (NNT 2.1; 95% confidence interval ) was as effective as 400 mg standard ibuprofen (NNT 2.4; 95% CI ), with faster onset of analgesia. More rapid absorption, faster initial pain reduction, good overall analgesia in more patients at the same dose, and probably longer-lasting analgesia, but with no higher rate of patients reporting adverse events. However, earlier onset preferred in other pain condition, such as chronic nociceptive or neuropathic pain? Peloso, P.M., Faster, higher, stronger: to the gold medal podium? Pain, (1): p Celecoxib Unfavorable cardiovascular risk profile associated with nonselective NSAIDs diclofenac and ibuprofen, not celecoxib Sondergaard KB, Weeke P, Wissenberg M, et al. Non-steroidal anti-inflammatory drug use is associated with increased risk of out-of-hospital cardiac arrest: a nationwide case-time-control study. Eur Heart J Cardiovasc Pharmacother Celecoxib compared to naproxen and ibuprofen: possibly better renal safety, similar cardiovascular safety Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis. N Engl J Med. 2016;375(26): COX-2 inhibitors significantly reduce risk of perforation, obstruction, bleeding, diarrhea, and withdrawal due to GI adverse events, while risk of dyspepsia was lower with NSAIDs plus PPI. Jarupongprapa S, Ussavasodhi P, Katchamart W. Comparison of gastrointestinal adverse effects between cyclooxygenase-2 inhibitors and nonselective, non-steroidal anti-inflammatory drugs plus proton pump inhibitors: a systematic review and meta-analysis. J Gastroenterol. 2013;48(7):830-8.

13 NSAIDs for Neuropathic Pain No RCTs Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. The Lancet. Neurology. Feb 2015;14(2): NSAIDs are so widely viewed as being ineffective for neuropathic pain that no major guidelines even mention them in their NSAIDs are commonly prescribed for neuropathic pain Dieleman JP, Kerklaan J, Huygen FJ, Bouma PA, Sturkenboom CJ. Incidence rates and treatment of neuropathic pain conditions in the general population. Pain 2008;137: algorithm.attal N, Cruccu G, Baron R, Haanpää M, Hansson P, Jensen TS, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010;17:1113-e88. Preclinical and clinical studies have demonstrated efficacy for NSAIDs in neuropathic pain states Vo T, Rice AS, Dworkin RH. Non-steroidal anti-inflammatory drugs for neuropathic pain: how do we explain continued widespread use? Pain 2009;143: ; Cohen KL, Harris S. Efficacy and safety of nonsteroidal anti-inflammatory drugs WHO Principle: Using a Two-Step Strategy WHO Step 1 Mild Pain WHO Step 2 Moderate to Severe Pain Morphine Ibuprofen and/or Acetaminophen (Paracetamol) Other NSAIDs? Cox-2 Inhibitor? or fentanyl, hydromorphone, oxycodone, methadone (UK: diamorphine) Multimodal (Opioid-sparing) Analgesia Basic Analgesics Acetaminophen / Paracetamol NSAIDs Integrative Therapies Such as: Massage Distraction Deep Breathing Biofeedback Aromatherapy Hypnosis Opioids Tramadol ( weak ) Morphine ( strong ) 4 WHO- Principles By the clock Psychology CBT Rehabilitation Exercise, Physical Therapy Sleep Hygiene OT

14 Analgesic Response Patients differ in their response to opioid analgesics Even in well designed, successful clinical trials, as much as 40% of patients do not respond well to analgesic being studied Argoff CE, Yanni LM. Pharmacogenetics and pain. Prim Care Q 2010;1-8 Unsurprising, patients may require trials of several opioids to find effective analgesia with acceptable tolerability μ-receptor Subtypes Individuals display variety of combinations of different mureceptor subtypes Generated through alternative splicing, known to enhance protein diversity Binding profiles & resulting pharmacologic effects of opioid receptor subtypes vary among μ-opioids dimer of μ receptors. Credit: Kobilka lab Contributing to individual variance in therapeutic response & incomplete cross-tolerance Review Brennan MJ. The clinical implications of cytochrome p450 interactions with opioids and strategies for pain management. Journal of Pain and Symptom Management Dec;44(6 Suppl):S Expect analgesic failure: pursue analgesic success Most analgesic drugs work well but in only a small percentage of people Pain relief not normally distributed but usually bimodal, being either very good (above 50%) or poor (below 15%) need to move away from focus on average response and seek out what works for each patient

15 Myths and Barriers to Using Opioids Case Scenario: You are taking care of a child with severe acute somatic nociceptive pain (e.g. cancer, sickle-cell crisis, major burn etc.). It crosses your mind to administer a strong opioid such as morphine What would be the most common concerns you might hear from your colleagues or parents arguing against opioid use in this child? Common Opioid Assumptions Addiction chronic relapsing condition characterized by persistent, compulsive dependence on a behavior or substance despite adverse consequences Tolerance addiction Pseudo-addiction Over Sedation / Respiratory Depression Ileus / Constipation Medication Too strong Masking symptoms Abdominal Pain Ranji SR, Goldman LE, Simel DL, Shojania KG. Do opiates affect the clinical evaluation of patients with abdominal pain? JAMA 2006: 296: Opioids after major cranial surgery in children do NOT result in altered mental status nor respiratory depression Maxwell LG. PAIN MANAGEMENT FOLLOWING MAJOR INTRACRANIAL SURGERY IN PEDIATRIC PATIENTS: A PROSPECTIVE COHORT STUDY IN THREE ACADEMIC CHILDREN S HOSPITALS Pediatric Critical Care Medicine: May Volume 15 - Issue 4_suppl - p 77. Abstracts of the 7th World Congress on Pediatric Critical Care As always... Think first!(e.g. compartment syndrome?)... analgesia second... So, what amount of opioid prescribing is appropriate?

16 Which Opioid to choose? Scrubs Case Example Lexi 7-year-old girl in severe acute (!) pain; weight: 20 kg PCA pump currently not available Immediate release morphine...unless... Choice of opioid? Case Example Morphine Route of administration? Per kg dosing: Maximum 50 kg (!) Lean weight for obese children Please write the order (small group work)

17 Case Example Morphine (Immediate Release) Scheduled (round-the-clock) dose IV: 0.1 mg x 15 kg = 2 mg Q4h PO: 0.3 mg x 15 kg = 6 mg Q4h (= 12 mg/day) (= 36 mg/day) Breakthrough (rescue) dose = 1/10-1/6 of daily dose (Q1-2h) IV: (1.2-2 mg) 1.2 mg Q1h PRN PO: (3.6-6 mg) 3.6 mg Q1h PRN if pain score >...?.../10 and no signs of over sedation Case Example Morphine 0300 hrs: Pain Score 10/10 -> 2 mg IV [or 6 mg PO] 0700 hrs: Pain Score 5/10...??? Do I need to increase the dose? 0400 hrs: Pain Score 8/10) -> 1.2 mg IV [or 3.6 mg PO] 0500 hrs: Pain Score 7/10 -> 1.2 mg IV [or 3.6 mg PO] 0600 hrs: Pain Score 6/10 -> 1.2 mg IV [or 3.6 mg PO] Crystal clear answer: Opioid Dose Escalation for Acute (!) Pain How to increase the dose?

18 Opioid Dose Escalation for Acute (!) Pain How to increase the dose? 50 per cent rule!...however, depends on clinical scenario mg IV Q1 (-2)h PRN - > 1.8 mg IV Q1 (-2)h PRN or...add breakthrough dose to regular dose...? [not initial hours] 2 mg IV Q4h -> 3 mg IV Q4h Lexi, 3 Days Later. Scheduled oral immediate release morphine: 13 mg Q4h (= 78 mg/day) Breakthrough (rescue) dose for incidence pain (PT) only 10 mg x 3 / day She doesn t like to be woken up Q4h... Change to extended-release morphine: 40 mg twice per day [occasionally end-of-dose failure: then Q8h] Continue breakthrough dose 10 mg Q1-2H PRN Extended (Sustained) Release Opioids USA: Morphine, Oxycodone, Hydromorphone [oxymorphone, hydrocodone, tramadol] Do not cut nor crush tablets/ capsules Do not store in liquids However, outside USA: Morphine extended-release sachets (powder) to be dissolved in liquid

19 Switching Opioids Differences between opioids in the balance between analgesic cross-tolerance level and the level of cross-tolerance to adverse effects can be exploited to clinical advantage. Switching opioids can possibly achieve a more favorable balance between analgesia and adverse effects, hence the rationale for trial of a different opioid in the event of toxicity or inadequate analgesia. Lawlor P (2001) Dose Ratios Among Different Opioids. In: Bruera E, Portenoy RK (ed) Topics in Palliative Care Vol 5; Oxford University Press, pp Analgesia Side effects Side effects Analgesia Problems with Equianalgesic Tables? (Real life example) 10 mg IV Morphine = 1.5 mg Hydromorphone? 1.5 mg Hydromorphone = 10 mg IV Morphine? 50 mcg/hour [0.05mg] IV Fentanyl = 5 mg IV/hour Morphine???? Suggested Opioid Conversion The rough (!) guide Oxycodone PO 3:1 3mg PO = 1mg IV 1 : 2 1mg IV = 2 mg PO Oxycodone PO 1.5 : 1 3 mg PO Morphine = 2 mg PO Oxycodone Morphine PO 5 : 1 5 mg PO Morphine = 1 mg PO Hydromorphone Hydromorphone PO 5 : 1 5mg PO = 1mg IV 1 : 1 3 mg PO Oxycodone = 3 mg PO Morphine 1 : 4 1 mg PO Hydromorphone = 4 mg PO Morphine 1 : mg IV = 3.5 mg PO Hydromorphone IV 3 : 1 3mg PO = 1mg IV 1 : 5 1 mg IV Hydromorphone = 5 mg IV Morphine I.V. Morphine I.V. Morphine Intravenous Morphine I.V. Morphine I.V. Morphine 1 : 3 1mg IV = 3 mg PO Morphine PO Clinical Context Incomplete Cross Tolerance: Decrease dose by (0-33% -) 50% (or more?) 7 : 1 7 mg IV Morphine = 1 mg IV Hydromorphone Hydromorphone IV Fentanyl IV 1 : mcg IV Fentanyl = 1000 mcg [1mg] IV Morphine Infants 1 : mcg IV Fentanyl 40 : 1 1 mg [1000 mcg] IV Morphine = 25 mcg IV Fentanyl Fentanyl IV = mcg [ mg) IV Morphine Friedrichsdorf SJ: 10th Pediatric Pain Master Class, Minneapolis, MN, June 17-23, 2017

20 Methadone Conversion- The 30 mg Table... actually 60mg... reduced by 50-75% for incomplete cross tolerance Starting Dose (Opioid Naïve): mg/kg/dose [2.5-5 mg PO Q6-12] Conversion Ratio: Total Daily Oral Morphine Dose Estimated Daily Oral Methadone Requirement Gazelle G, Fine PG. Methadone for the treatment of pain #75. J Palliat Med. 2003;6(4): ROXANE LABORATORIES, INC. Columbus, OH drugsatfda_docs/label/ 2006/006134s028lbl.pdf Toombs JD (2005) Americ Family Physician 71(7): < 100 mg 3:1 20% - 30% 33 % 101mg - 300mg 5:1 10% - 20% 20 % 301mg - 600mg 10:1 8% - 12% 10 % 601mg - 800mg 12:1 5% - 10% 8 % 801mg mg 15:1 5% - 10% 7 % > 1000mg 20:1 < 5 % 5 % Opioids for neuropathic pain Simple Analgesia (NSAIDs) Weak opioid: Tramadol Dose: 1-2 mg/kg Q4-6 hours, max 8mg/kg/day (adult mg q 4-6h, max 400mg/ day) Not in children with seizure disorder Strong opioids morphine, fentanyl, hydromorphone, oxycodone, or methadone (adult) NNT: 4.3 Methadone as First Line Opioid Methadone may be effective as firstline drug in the management of cancer pain, providing analgesia and adverse effect profiles similar to those produced by other opioids Mercadante S, Bruera E. Methadone as a First- Line Opioid in Cancer Pain Management: A Systematic Review. J Pain Symptom Manage. 2018;55(3): HOT OFF THE * PRESS * doses tend to remain stable suggests that metabolic characteristics and extraopioid analgesic effects, as its well antihyperalgesic properties may be interesting potential advantages Starting Dose (Opioid Naïve): mg/kg/dose [2.5-5 mg PO Q6-12]

21 Blog: Cardiac Toxicity of Methadone: Predictors of QTc prolongation: hypokalemia, rheumatologic disorders, use of medications with a known torsades de pointes risk, malignancy, hypocalcemia, and methadone doses >45 mg per day (Mild liver disease was protective) Juba KM, Khadem TM, Hutchinson DJ, Brown JE. Methadone and Corrected QT Prolongation in Pain and Palliative Care Patients: A Case- Control Study. J Palliat Med. 2017;20(7): case reports: Low-dose Methadone mg/kg/dose BID effective to treat refractory neuropathic pain in 2 children with cancer. Madden K, Bruera E. Very-Low-Dose Methadone To Treat Refractory Neuropathic Pain in Methadone HOT OFF THE * PRESS * Children with Cancer. J Palliat Med. 2017;20(11): Further Training Contact: CIPPC@ChildrensMN.org SAVE THE DATE: 12th International Symposium on Pediatric Pain (ISPP) in Basel, Switzerland, June 16-20, Education in Palliative & End-of-life Care (EPEC) Pediatrics: Become an EPEC-Pediatrics Trainer Conference, Oct 2-4, 2019 plus optional EPEC-Pediatrics Professional Development Workshop: Oct 5, th Pediatric Pain Master Class in Minneapolis, MN, June 13-19, 2020 Stefan J. Friedrichsdorf, MD, FAAP Medical Director, Department of Pain Medicine, Palliative Care & Integrative Medicine Associate Professor of Pediatrics, University of Minnesota Medical School Children's Hospitals and Clinics of Minnesota 2525 Chicago Ave S Minneapolis, MN USA phone fax stefan.friedrichsdorf@childrensmn.org