01 Advanced Pain FRIEDRICHSDORF.key

Stefan J. Friedrichsdorf, MD, FAAPMedical Director, Department of Pain Medicine, Palliative Care & Integrative MedicineChildren's Hospitals and Clinics of Minnesota, Minneapolis/St. Paul, MN

Associate Professor of Pediatrics, University of Minnesota Medical School

[email protected] Twitter: @NoNeedlessPain

Advanced Pain Treatment for Children with Serious Illness: From Myths, Magic, Morphine to Multimodal Analgesia Fortgeschrittene Schmerztherapie für Kinder mit schweren Erkrankungen: Von Mythen, Magie, Morphin und multimodaler Analgesie

Minneapolis / St. Paul (Minnesota)

FUN FACTS Minneapolis, Minnesota: • City of 10 Lakes (& 187 parks!); 3.5 million people in metro• Snowy winter, groovy spring, summer & fall• Minnesota home to 19 Fortune 500 companies, more than any other state• America’s most literate city• Biggest shopping mall in US• Most theater seats after New York City• Children’s Minnesota: 10th largest in US, 385 beds, 50% ICU• Our department: 33.6 FTE

Learning Objectives

• Evaluate assumptions about opioid use in children [“Attitude”]

• Discuss how multiple agents, interventions, rehabilitation, psychological & integrative therapies act synergistically for more effective pediatric pain control with fewer side effects than a single analgesic or modality - and improves patient experience [“Knowledge”]

• Develop Step-by-step approach for neuropathic pain management [“Skill”]

5-year old Marius: Procedural Pain Management

”Redningskvinder” Channel Tv3 - Http://Www.Tv3.Dk/Redningskvinder. (Episode 7, Season 4.) 2014

Pediatric Analgesia in 1985 “Papoose Boards”

Don't have enough staff for pediatric pain control...?

Funny, how there is

always enough staff to restrain a child.

Symptom prevalence and distress reported by children with advanced cancer

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 2015.

Outcomes Improved 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 et al. J Palliat Med 2015

• 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, 2015. 62(8): p. 1409-13.

• 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, 2015. 136(5): p. 938-46.

Pediatric Pain - Status Quo

• Under treatment of pain in children

• Parents expect pain to be relieved Forgeron PA, Finley GA, Arnaout M. Pediatric pain prevalence and

parents' attitudes at a cancer hospital in Jordan. J Pain Symptom Manage. 2006; 31(5):440-8.

• Priorities of parents of hospitalized children "Taking care of pain" rated as second highest priority (1st: getting right diagnosis) Ammentorp J, Mainz J, Sabroe S. Parents’

priorities and satisfaction with acute pediatric care. Arch Pediatr Adolesc Med 2005;159:127-131

• Parents’ greatest distress: failing to protect their child from pain Tiedeman, M. (1997). Anxiety responses of parents during and

after the hospitalisation of their 5 - to -11 year old children. Journal of Pediatric Nursing, 12(2), 110-119. Melnyk BM. Intervention studies involving parents of hospitalized young children: an analysis of the past and future recommendations. J Pediatr Nurs. 2000 Feb;15(1):4-13.

• Assumption: everything possible is done Anand’s neonatal surgery studies

Pediatric Pain - Status Quo

• USA: adults receive more than two - three times as many analgesic doses as children (with identical diagnoses) (1) Eland JM, Anderson JE: The experience of pain in

children. In: Jacox A (ed). Pain: a source book for nurses and other health care professionals. Boston: Little Brown & C0; 1977:453-78 (2) Beyer JE, DeGood DE, Ashley LC, Russell GA. Patterns of postoperative analgesic use with adults and children following cardiac surgery. Pain. 1983 Sep;17(1):71-81. (3) Schechter NL, Allen DA, Hanson K. Status of pediatric pain control: a comparison of hospital analgesic usage in children and adults. Pediatrics. 1986 Jan;77(1):11-5.

• Compared to adults, pediatric patients receive fewer and/or incorrectly dosed analgesics in daily routine Ellis, J. A., O’Connor, B. V., Cappelli, M., Goodman, J., Blouin, R.,

& Reid, C. W. (2002). Pain in hospitalized pediatric patients: How are we doing? Clinical Journal of Pain, 18, 262-269.

• The younger children are, the less likely they receive appropriate analgesia Broome ME,

Richtsmeier A, Maikler V, Alexander M. Pediatric pain practices: a national survey of health professionals. J Pain Symptom Manage. 1996 May;11(5):312-20.; Nikanne E, Kokki H, Tuovinen K. Postoperative pain after adenoidectomy in children. Br J Anaesth. 1999 Jun;82(6):886-9.

Inappropriate Analgesia: Why Bother...?

• Children with persistent pain suffer more physical symptoms in adult life, more anxiety and more depression 1946 Medical Research Council and 1958 National Child

Development Study

• Inadequate analgesia for initial procedures in children diminishes effect of adequate analgesia in subsequent procedures Weisman SJ, Bernstein B,

Schechter NL: Consequences of inadequate analgesia during painful procedures in children. Arch Pediatr Adolesc Med 1998. 152:147-9

• NICU: increased morbidity & mortality Anand KJ, Barton BA, McIntosh N, Lagercrantz H, Pelausa E, Young TE,

et al. Analgesia and sedation in preterm neonates who require ventilatory support: results from the NOPAIN trial. Neonatal Outcome and Prolonged Analgesia in Neonates. Arch Pediatr Adolesc Med. 1999 Apr;153(4):331-8

• Higher morphine doses = less PTSD in months after major trauma Stoddard FJ, Jr., Sorrentino EA, Ceranoglu TA, Saxe G, Murphy JM, Drake JE,

et al. Preliminary evidence for the effects of morphine on posttraumatic stress disorder symptoms in one- to four-year-olds with burns. J Burn Care Res. 2009 Sep-Oct;30(5):836-43.

• Up to 25% of adults have fear of needles with most fears developing in childhood: avoidance of health care (including non-adherence with vaccination schedules Taddio A, Chambers CT, Halperin SA, et al. Inadequate pain

management duringchildhood immunizations: the nerve of it. Clin Ther 2009;31(Suppl 2):S152-67.)

So, how do we treat the individual pain patient in front of us ?

Hmhh...Spoiler Alert: Crystal-clear answer on 3rd last slide!

Myths and Barriers to Using Opioids

Case Scenario:

• You are taking care of a child in a hospital with severe acute somatic nociceptive pain. It crosses your mind to administer a strong opioid such as morphine, fentanyl, or hydromorphone.

• 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: 296:1764-74

• 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 2014 - 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...

How Do We Manage Acute Pain in Children?

Multimodal AnalgesiaNo Needless Pain: The Children’s Comfort Promise

https://vimeo.com/20329079

• Dosing at regular intervals (“By the Clock”)

• Adapting treatment to the individual child (“With the Child”)

• Using the appropriate route of administration (“By the appropriate route)

• Using a two-step strategy (“By the Analgesic Ladder”)

WHO guidelines on the pharmacological treatment of persisting pain in children with medical illnesses (2012)

http://whqlibdoc.who.int/publications/2012/9789241548120_Guidelines.pdf

WHO Principle 1: Dosing at Regular Intervals

• PRN (pro re data =“as needed”)

• PRN = Patient Receives Nothing

• When pain is constantly present, analgesics should be administered, while monitoring side-effects, at regular intervals

• “By the clock” and NOT as an “as needed” (or pro re nata “PRN”) basis

• Regular scheduling ensures a steady blood level, reducing the peaks and troughs of PRN (“as needed”) dosing

• PRN (as needed) only:

• May take several hours & higher opioid doses to relieve pain

• Results in cycle of undermedication and pain, alternating with periods of overmedication and drug toxicity American Pain Society: Principles of Analgesic Use in the Treatment

of Acute Pain and Cancer Pain 2008. 24-27

Scheduling Analgesia“It Is After 10, Give My Daughter The Pain Shot…” (Shirley Maclaine: Terms Of Endearment, 1983)






WHO Principle 2: Adapting Treatment to the Individual Child

• Treatment should be tailored to the individual child and opioid analgesics should be titrated on an individual basis

• At analgesic dosing: no sedation expected

• The effective dose is what relieves the pain

• Different children may respond differently to same dose

• Effective dose must be adjusted to child’s needs

• Dose of strong opioids: only the sky is the limit

• Assess response frequently

• Pain Scales

• Look for opioid-induced side effects and toxicity

Regular (!) Pain Assessment

• One-dimensional self-report scores

• Multi-dimensional rating scores

What are we measuring...?

(1) Nociceptive Pain: arises from the activation of peripheral nerve endings (nociceptors) that respond to noxious stimulation

• Somatic (for example, muscles, joints)

• Chronic somatic pain typically well localized & often results from degenerative processes (such as arthritis)

• Visceral (internal organs)

(2) Neuropathic Pain: resulting from injury to, or dysfunction of, the somatosensory system.

• Central pain: caused by a lesion or disease of the central somatosensory nervous system

(3) Psycho-social-spiritual-emotional Pain / Total Pain

(4) Chronic Pain

• Pain beyond expected time of healing

Pain in children with impaired communication

• Non-communicating Children’s Pain Checklist - Revised (NCCPC-R); postoperative Version (NCCPC-PV) Breau LM, McGrath PJ, Camfield

CS, Finley GA. Psychometric properties of the non-communicating children's pain checklist-revised. Pain 2002;99(1-2):349-357.

• Pediatric Pain Profile (PPP) Hunt A, Goldman A, Seers K, Crichton N,

Mastroyannopoulou K, Moffat V, Oulton K, Brady M. Clinical validation of the paediatric pain profile. Dev Med Child Neurol 2004;46(1):9-18.

• r-FLACC Malviya S, Voepel-Lewis T, Burke C, Merkel S, Tait

AR. The revised FLACC observational pain tool: improved reliability and validity for pain assessment in children with cognitive impairment. Paediatr Anaesth 2006;16(3):258-265.

High specificity, low sensitivity…? Don’t forget:

• Withdrawal: WAT-1 score Franck, L et al, (2008) Ped Crit Care Med, Vol 9, no. 6 http://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, 2014. 42(3): p. 656-63.

• 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, 2006. 7(2): p. 107-14.

Measuring pain alone…?

Pain AssessmentScrubs (German)






WHO Principle 3: Route of Administration

orali.v. / s.c. intranasal (MAD device)

nebulization?

suppositorytransdermal

i.m.

sublingual

transmucosal

Analgesic Medications






WHO Principle 4: Using a Two-Step Strategy

WHO Step 1Mild Pain

Ibuprofenand/or

Acetaminophen(Paracetamol)

Other NSAIDs?Cox-2 Inhibitor?


Aδ or C fiber Injury

Thalamus

NSAIDs

Acetaminophen (Paracetamol)

2nd Neuron

Nociceptive Pathways & Primary Sites of Action of Analgesics

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, 2014. 155(1): p. 14-21.

• e.g. Advil® Film-Coated Tablets: 266 mg ibuprofen sodium (= 200 mg of standard ibuprofen)

• Produced significantly better analgesia over 6h, fewer re-medications than standard formulations

• 200-mg fast-acting ibuprofen (NNT 2.1; 95% confidence interval 1.9-2.4) was as effective as 400 mg standard ibuprofen (NNT 2.4; 95% CI 2.2-2.5), 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, 2014. 155(1): p. 4-5.

WHO Principle 1: Using a Two-Step Strategy

WHO Step 1Mild Pain

Ibuprofenand/or

Acetaminophen(Paracetamol)

Other NSAIDs?Cox-2 Inhibitor?

Morphine

or fentanyl,

hydromorphone, oxycodone, methadone

WHO Step 2Moderate to Severe Pain

Aδ or C fiber


Injury

Thalamus

NSAIDs


2nd Neuron

Opioids

Non-Opioids• Acetaminophen / Paracetamol• NSAIDs

Multimodal (Opioid-sparing) Analgesia

Integrative TherapiesSuch as:• Massage• Distraction• Deep Breathing• Biofeedback• Aromatherapy• Hypnosis

Opioids• Tramadol („weak“)• Morphine („strong“)

4 WHO-Principles• “By the clock”

Integrative Pain ManagementState of the art pain management in the 21st century demands that pharmacological management must be combined with supportive and integrative, non-pharmacological therapies to manage a child's pain.

• Physical methods (e.g. cuddle/hug, massage, comfort positioning, heat, cold, TENS)

• Cognitive behavioral techniques (e.g. guided imagery, hypnosis, abdominal breathing, distraction, biofeedback)

• Acupuncture, acupressure, aromatherapy

"Healing Environment" Pain, Palliative & Integrative Medicine Clinic

https://vimeo.com/122654881

Integrative Pain & Symptom Management

• A Pediatrician’s Top 10 Apps for Distraction & Pain Management http://NoNeedlessPain.org

Stationary Children’s HospiceBear Cottage, Sydney, Australia

Stationary Children’s HospiceBear Cottage, Sydney, Australia

Pediatric Clinical Hypnosis Training

Introductory - Intermediate - Advanced Levels

National Pediatric Hypnosis Training Institute (formerly associated with the SDBP)

www.nphti.org

Pediatric Hypnosis Workshops Minneapolis

Aδ or C fiber


Injury

Thalamus

NSAIDs


2nd Neuron

Opioids

Periaqueductalgrey (endorphins)

Descending

Inhibition

+

Integrative (non-pharmacological)

therapies

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.

How does this stuff work...?

• The periaqueductal gray and descending pain modulation: Hemington KS,

Coulombe MA. The periaqueductal gray and descending pain modulation: Why should we study them and what role do they play in chronic pain? Journal of neurophysiology. Feb 11 2015:jn 00998 02014.

• Distraction significantly increased activation of cingulo-frontal cortex including orbitofrontal & perigenual anterior cingulate cortex (ACC), as well as periaquaeductal gray (PAG) & the posterior thalamus.

• Active distraction techniques, such as imagery, appear to modulate endorphine release in the midbrain, including the periaqueductal grey and thereby increase activity of descending inhibiting pathways thereby decreasing nociception from the dorsal horn resulting in gate pain modulation during distraction. Valet M,

Sprenger T, Boecker H, et al. Distraction modulates connectivity of the cingulo-frontal cortex and the midbrain during pain--an fMRI analysis. Pain. Jun 2004;109(3):399-408.; Tracey I, Ploghaus A, Gati JS, et al. Imaging attentional modulation of pain in the periaqueductal gray in humans. The Journal of neuroscience : the official journal of the Society for Neuroscience. Apr 1 2002;22(7):2748-2752.; Derbyshire SW, Osborn J. Modeling pain circuits: how imaging may modify perception. Neuroimaging clinics of North America. Nov 2007;17(4):485-493, ix.; Bingel U, Wanigasekera V, Wiech K, et al. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci Transl Med. Feb 16 2011;3(70):70ra14

Aδ or C fiber


Injury

Thalamus

NSAIDs


2nd Neuron

Opioids


“OFF”


therapies

“ON”

CORTEX:-Stress- Anxiety- Catastrophizing- Depression- perceived injustice- disturbed Sleep

Non-Opioids• Acetaminophen / Paracetamol• NSAIDs

Multimodal (Opioid-sparing) Analgesia Friedrichsdorf S: 9th Annual Pediatric Pain Master Class, Minneapolis, MN, June 11-17, 2016

Integrative TherapiesSuch as:

• Massage• Distraction• Deep Breathing• Biofeedback• Aromatherapy• Hypnosis

OpioidsSuch as:• Tramadol („weak“)• Morphine („strong“)

4 WHO-Principles• “By the clock”

AdjuvantsSuch as:• Alpha-Agonist• Gabapentinoids • TCA/Antidepressants• NMDA-Antagonists• Na-channel blockers• Antispasmodics• Benzodiazepines• Corticosteroids• Muscle relaxants• Radiopharmaceuticals • Bisphosphonates

Regional Anesthesia• Neuraxial infusion• Peripheral/Plexus Nerve block• Neurolytic block• Intrathecal port/pump• Intraventricular opioids?• Percutaneous cervical cordotomy?

Rehabilitation• Exercise, Physical Therapy• Sleep Hygiene• OT

Psychology• CBT

Spirituality

Is it Neuropathic 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, 46:305-10

• 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;85-460-2

• 275 children with progressive, non-curable genetic, metabolic, or neurological conditions: Pain 53% [Most of the time: 21.8 %] Steele R, Siden H, Cadell S, et al. Charting the territory:

symptoms and functional assessment in children with progressive, non-curable conditions. Arch Dis Child. Aug 2014;99(8):754-762.

• Some genetic factors underlying development of neuropathic pain and chronic widespread pain are the same Momi, S.K., et al., Neuropathic pain as part of chronic widespread pain: environmental and genetic influences. Pain, 2015. 156(10): p. 2100-6.

Let’s get started…

Potential Causes Include

• Spinal cord injury: “pain arising as a direct consequence of affecting the somatosensory system”

• Tumor related: direct tissue and nerve injury; advanced unresectable solid tumors

• Phantom limb pain: 60 - 80% of adult patients with amputation experience phantom sensations in their amputated limb, majority are painful Sherman RA., Sherman CJ, Parker L. Chronic phantom and stump pain among American veterans: Results of a survey". Pain. 1984;18: 83–95.

• Autoimmune and degenerative neuropathies: Guillain-Barré syndrome; Charcot-Marie-Tooth disease Walco GA, Dworkin RH, Krane EJ, LeBel AA, Treede RD. Neuropathic pain in children: Special considerations. Mayo Clin Proc. 2010;85(3 Suppl):S33-41

Potential Causes Include

• Metabolic neuropathies: toxic and metabolic neuropathies (eg, lead, mercury, alcohol, infection)

• Neurodegenerative disorders: Hereditary neurodegenerative disorders (Fabry disease, X-linked lysosomal disease caused by deficiency α-galactosidase), mitochondrial disorders, and primary erythromelalgia

• Cancer-directed chemotherapy, including

• Vincristine: 50% painful peripheral neuropathy, muscle camps, numbness, tingling (hand, feet)

• Cisplatin: Paresthesias in extremities

Pinky speaks for Nadia Pain Assessment

Case Report: Henry• 11-year-old, relapsed T-cell

lymphoma, weight: 52 kgs

• Onset of chemotherapy-induced bi-pedal neuropathy VAS 9/10

• Abdominal pain (hemorrhagic cystitis)

• Unresponsiveness versus over sedation

• Autonomic changes at feet

(1) Identify and treat underlying disease process (radiation?) (corticosteroids?)

(2) Integrative therapies & Rehabilitation: manage comorbidities (anxiety, sleep disturbances). Psychological Therapies.

Management of Neuropathic Pain in Pediatrics Suggested “Non-Evidence-based” Step-by-Step Approach

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, 2015. 156(9): p. 1812-25.

• Behavioral (deep breathing, imagery, hypnosis, smart-phone/tablet “apps”)

• Acupressure, acupuncture, aromatherapy

Case Report: Henry• Integrative, supportive,

rehabilitative therapies

• Behavioral Therapies

• Breathing

• Imagery

• Hypnosis

• Individual Psychotherapy

• Physical Therapy

• TENS

• Exercise

• Stockings

• Make-a-wish


(3) Regional anesthesia, if appropriate



Regional anesthesia approaches to pain management in PC

• Regional anesthesia: pediatric knowledge limited to case reports and case series: Rork, J.F., C.B. Berde,

and R.D. Goldstein, Regional anesthesia approaches to pain management in pediatric palliative care: a review of current knowledge. J Pain Symptom Manage, 2013. 46(6): p. 859-73.

• central neuraxial infusions

• peripheral nerve and plexus blocks or infusions

• neurolytic blocks

• implanted intrathecal ports & pumps for baclofen, opioids, local anesthetics, and other adjuvants

• Neurolytic Sympathectomy: Amr YM, Makharita MY.

Neurolytic sympathectomy in the management of cancer pain-time effect: a prospective,

randomized multicenter study. J Pain Symptom Manage. Nov 2014;48(5):944-956 e942.

• RCT (n=109) inoperable abdominal or pelvic cancer: better pain control, less opioid consumption, and better quality of

life


(4) NEW (!) onset: Opioid analgesics [consider Tramadol or Methadone] plus NSAID




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):162-173.

• NSAIDs are so widely viewed as being ineffective for neuropathic pain that no major guidelines even mention them in their 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;143:169-71.; Cohen KL, Harris S. Efficacy and safety of nonsteroidal anti-inflammatory drugs

• 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;137:681-8.

Opioids for Neuropathic Pain

“Weak” opioids (= multimechanism)

• Tramadol NNT 4.7; NNH 6.3 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):162-173.

• Tapentadol? Bias; NNT 10.2

“Strong” Opioids

• Morphine, oxycodone NNT 4.3; NNH 11.7 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):162-173.

• No additional benefit > 180 mg morphine equivalent

• Cochrane analysis: Oxycodone NOT effective as a pain medicine in diabetic neuropathy or postherpetic neuralgia Gaskell H, Moore RA, Derry S, Stannard C. Oxycodone for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2014;6:CD010692.

Case Report: Henry• COX-2-INHIBITOR: Celecoxib

200 mg BID

• OPIOID: Hydromorphone PCA 1.35 mg/hr (max. 52 boluses/day [1.35mg])

• Rotation: Methadone 30 mg/day [5 mg IV Q4h -> 10 mg IV Q8h] plus Hydromorphone PCA bolus 2mg IV, lockout 10 minutes

• Methadone PO 10 mg TID -> 12.5 mg TID



(5) Tricyclic Antidepressant (or gabapentinoid) ± low-dose ketamine




Case Report: Henry

(1) TRICYCLIC ANTIDEPRESSANT

• Amitriptyline 5 mg -> 25 mg QHS

(2) Ca-channel α2-δ ligand

• Pregabalin 50 mg QHS -> 300 mg BID

(3) CORTICOSTEROID

• Dexamethasone 10 mg BID

(4) LIDOCAINE

• 5% patches Q12h on/off

Amitriptyline• NNT: 3.6; NNH: 13.4 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):162-173.

• No dose-response effect

• Nortriptyline: only 1 study

• Efficacy of TCA in central pain Rintala DH, Holmes SA, Courtade D, Fiess RN, Tastard LV, Loubser PG. Comparison of the effectiveness of amitriptyline and gabapentin on chronic neuropathic pain in persons with spinal cord injury. Archives of physical medicine and rehabilitation.. 2007 Dec;88(12):1547-60.

• n=39; superior efficacy of a nortriptyline-morphine combination over either monotherapy (plus gabapentionoid?) Gilron, I., et al., Combination of morphine with nortriptyline for neuropathic pain. Pain, 2015. 156(8): p. 1440-8.

• 2 studies (high effect size): no effect of amitriptyline in HIV neuropathy Kieburtz K, Simpson D, Yiannoutsos C, Max MB, Hall CD, Ellis RJ, et al. A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection. AIDS Clinical Trial Group 242 Protocol Team. Neurology. 1998 Dec;51(6):1682-8. Shlay JC, Chaloner K, Max MB, Flaws B, Reichelderfer P, Wentworth D, et al. Acupuncture and amitriptyline for pain due to HIV-related peripheral neuropathy: a randomized controlled trial. Terry Beirn Community Programs for Clinical Research on AIDS. JAMA.1998 Nov 11;280(18):1590-5.

Aδ or C fiber


Injury

Thalamus

NSAIDs


2nd Neuron

Opioids


Descending

Inhibition

+


therapies

TCA SSRIs

Methadone Tramadol

Tricyclic Antidepressants:(+) Opioid analgesia via serotoninergic mechanism at brainstem




(6) Tricyclic Antidepressant and gabapentinoid




Case Report: Henry





(3) CORTICOSTEROID


(4) LIDOCAINE


Presynaptic nerve terminal

Postsynaptic nerve terminal

Glutamate Substance P

Voltage-gated Ca-channel

α2-δ subunit [dysfunction?/upregulation role in neuropathic pain]

G

Gabapentinoids: Ca-channel α2-δ ligands

Gabapentin

• Gabapentin: NNT: 6.3; NNH: 25.6

• Extended-release gabapentin: NNT 8.3; NNH 31.9 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):162-173.

• No dose-response effect

• 15 studies (1468 participants) (post-herpetic neuralgia, diabetic neuropathy, cancer related neuropathic pain, phantom limb pain, Guillain Barré syndrome, spinal chord injury pain, various neuropathic pains) Wiffen PJ, McQuay HJ, Edwards JE, Moore RA. Gabapentin for acute and chronic pain. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD005452.

• 42% improved compared to 19% on placebo

• NNT for effective pain relief in diabetic neuropathy 2.9; post herpetic neuralgia 3.9

Pregabaline

• Efficacy worse than gabapentin

• NNT: 7.7; NNH: 13.9 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):162-173.

• Dose-response (600mg/day more effective than 300 mg/day)

• Linear (pregabalin) versus non-linear (gabapentin) bioavailability: Clinical relevance unclear.

• Negative RCTs: HIV neuropathy; central post-stroke pain (1) Simpson DM, Schifitto G, Clifford DB, Murphy TK, Durso-De Cruz E, Glue P, et al. Pregabalin for painful HIV neuropathy: a randomized, double-blind, placebo-controlled trial. Neurology. 2010 Feb 2;74(5):413-20.; (2) Kim JS, Bashford G, Murphy TK, Martin A, Dror V, Cheung R. Safety and efficacy of pregabalin in patients with central post-stroke pain. Pain. 2011 May;152(5):1018-23.

• Adverse effects include: Weight increase, dizziness, somnolence, blurred vision, life-threatening angioedema (face, mouth, larynx) - careful concurrent administration with ACE inhibitors

Pediatric data

• 3 term & 8 preterm infants with suspected visceral hyperalgesia caused by variety of neurologic and gastrointestinal morbidities: Improved feeding tolerance and decreased irritability (2 bradycardia) Edwards, L., et al., Gabapentin Use in the Neonatal Intensive Care Unit. J Pediatr, 2016. 169: p. 310-2.

• Gabapentin appears to be an effective treatment for children with severe impairment of the CNS and recurrent pain behaviors, including intermittent changes in muscle tone. Hauer JM, Solodiuk JC. Gabapentin for management of recurrent pain in 22 nonverbal children with severe neurological impairment: a retrospective analysis. J Palliat Med. May 2015;18(5):453-456.

Aδ or C fiber


Injury

Thalamus

NSAIDs


2nd Neuron


Descending

Inhibition

+


therapies

TCA SSRIs

Methadone Tramadol

Opioids

Inhibitors of excitatory glutamate systems:

Gabapentin/Pregabalin Carbamazepine*

Valproate

Combination:Amitriptyline &

Gabapentin

Case Report: Henry





(3) CORTICOSTEROID


(4) LIDOCAINE






(7) Lidocain patch (if localized pain).




Case Report: Henry





(3) CORTICOSTEROID


(4) LIDOCAINE






(7) Lidocain patch (if localized pain).

(8) NMDA-receptor-channel blocker [ α- agonist? IV lidocaine? Botox A? benzodiazepine? SNRI? Capsaicin?]




Opioid induced tolerance and hyperalgesia

mu-receptor

Opioid

Gi/o proteins

Genes

Otherneuromodulators

Protein Kinase-C

stimulation

generation

activation

Alter responsecharacteristics of

neuron => Suppressneuronal excitability

uncoupling

Membrane Hyperpolarization

(K+ channel)

Inhibition of Ca channels: â

neurotransmitter release

Opioid induced tolerance and hyperalgesia

mu-receptor

Opioid

Gi/o proteins Proteine Kinase-C activation activation

NMDA-channelChen L, Nature 1992; 365:521-3

NMDA-Receptor Channel Blocker

• Central NMDA receptors

• Methadone reverses analgesic tolerance induced by morphine pretreatment (...at least in mice, that is…) Posa, L., et al., Methadone Reverses Analgesic Tolerance Induced by Morphine Pretreatment. Int J Neuropsychopharmacol, 2015

• NMDA receptors in supraspinal facilitatory sites (such as rostral ventromedial medulla, nucleus gigantocellularis) maintain non-inflammatory muscle pain in animal model Da Silva LF, Desantana JM, Sluka KA. Activation of NMDA receptors in the brainstem, rostral ventromedial medulla, and nucleus reticularis gigantocellularis mediates mechanical hyperalgesia produced by repeated intramuscular injections of acidic saline in rats. J Pain. 2010 Apr;11(4):378-87.

• Peripheral NMDA receptors

• topical 10% ketamine (compounded in pluronic lecithin organogel) reduced allodynia in CRPS. Adult RCT (n=20) Finch PM, Knudsen L, Drummond PD. Reduction of allodynia in patients with complex regional pain syndrome: A double-blind placebo-controlled trial of topical ketamine. Pain. 2009 Nov;146(1-2):18-25.

• Evidence: Dextromethorphan (6), Memantine (5), Mg (1): NNT 5.0; NNH 9.4 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):162-173.

• No ketamine evidence

Subanesthetic-dose Ketamine-PCA Day 1: 4 mg/hr [0.9 mcg/kg/min] plus 4 mg bolus

á 8 mg/hr [1.9 mcg/kg/min] plus 8 mg bolusDay 2: á 12 mg/hr [2.8 mcg/kg/min] plus 12 mg bolusDay 3: á 16 mg/hr [3.7 mcg/kg/min] plus 16 mg bolusDay 5: á 24 mg/hr [5.6 mcg/kg/min] plus 16 mg bolus

3 unsuccessful trials of decreasing/discontinuing dose

Day 8: Change to 40 mg PO PRNDay 10: 40 mg PO TID [plus 40 mg PRN]Day 14: Discontinued [changed to PRN only]

• Hypertonic at baseline, initially MAP increase by 10-15 mm/Hg• Absent benzodiazepine -> no psychotropic adverse effects

Case Report: Henry

Number of Hydromorphone PCA Boluses55 -> 20/day [â 64% over 3 days]

Opioid Use 71 mg/day -> 32 mg [â 55% over 4 days]

Pain Score:Bolus Response Hydromorphone: VAS 9/10 -> 7/10 Bolus Response Ketamine: VAS 9/10 -> 2/10

Usual Pain Scores: VAS 9/10 -> 2-3/10 [over 4 days]

Breakthrough Painâââ

Functionáá

Case Report: Henry

Methadone: 10 mg PO TID -> 12.5 mg PO TID -> 10 mg PO TID

Hydromorphone: 10 mg PO Q1h PRN (0-3/day)

Pregabalin: 300 mg BID

Amitriptyline: 25 mg QHS

Ketamine: 40 mg PO PRN Q1h ( discontinued after 2 weeks)

Lidocaine Patches: Discontinued after 3 weeks

Case Report: Henry at Home

Aδ or C fiber


Injury

Thalamus

NSAIDs


2nd Neuron


Descending

Inhibition

+


therapies

TCA SSRIs

Methadone Tramadol

Opioids

Inhibitors of excitatory glutamate systems:

Gabapentin/Pregabalin Carbamazepine*

Valproate

NMDA-Channel Blockers Ketamine Methadone

Stimulation of inhibiting GABA system

Baclofen Benzodiazepines

Valproate

Sodium-channel blockade

carbamazepine* lidocaine

CannabisSan Diego, CA

• AAP Handout for parents "Despite relaxed regulations, marijuana harms developing brain": http://aapnews.aappublications.org/content/36/3/4.full.pdf+html

• Updated AAP policy opposes marijuana use, citing potential harms, lack of research http://aapnews.aappublications.org/content/early/2015/01/26/aapnews.20150126-1

Crystal clear answer:

So, how do we treat the individual pain patient in front of us ?

Σωκράτη Sōkrátēs; 470/469 – 399 BC

Do you remember Marius...?How about a Plan B?

LET Anesthesia• Sitting upright

• Distraction

• Topical Anesthesia

• 3mL LET-gel: Lidocaine 4%-Epinephrine 0.18% -Tetracaine 0.5%

Singer AJ, Stark MJ. Pretreatment of lacerations with lidocaine, epinephrine, and tetracaine at triage: a randomized double-blind trial. Acad Emerg Med. 2000 Jul;7(7):751-6.

IV Access Under Nitrous Gas22 months-old, Lidocaine 4% cream in place, needed IV for radiologic procedure, history of challenging IV access in the past

Thanks to Patricia D. Scherrer MDChildren's Hospitals and Clinics of Minnesota

Pain Modulation Circuits

+

Off

On

+

Thalamus

Dorsal Horn

Cortex [cingulo-frontal, incl. orbitofrontal & perigenual anterior cingulate]

Periaquaeductal gray (PAG)

DRG

Des

cend

ing

Inhi

biti

ng P

athw

ay

Friedrichsdorf S: 9th Annual Pediatric Pain Master classMinneapolis, MN, Jun 11-17, 2016

Conclusions• Withholding evidence-based

analgesia from children in pain suffering from serious serious illnesses not only unethical, but causes immediate and long-term harm

• Potential risks in safety of analgesics are real, but manageable; cannot justify denying administration of pain medications to pediatric patients

• Neuropathic pain often under-assessed and under-treated

• Opioids (outside end-of-life) usually short term only - contraindicated for chronic pain

• Use multimodal (opioid-sparing) analgesia: Multiple agents, interventions, rehabilitation, psychological and integrative therapies act synergistically for more effective pediatric pain control with fewer side effects than single analgesic or modality

With profound gratitude to our interdisciplinary Pain, Palliative & Integrative Medicine team

Physician

• Kris Catrine, MD

• Kaci Osenga, MD

• Kathleen Farah, MD

• Stefan Friedrichsdorf, MD

• Matt Armfield, MD, Pain Fellow

• Meghan Young, MD, Palliative Care Fellow

Nurse Practitioner

• Barb Symalla, RN, CNS

• Nancy Jaworski, RN, CNS

• Kathy Popp, RN, CNS

• Sarah Thu, RN, CNS

• Anna Hoffman, RN, CNS

• Maura Fitzgerald, RN, CNP

• Jennifer Worley, RN, CNS

Psychology

• Kavita Desai, PhD

• Jade Raffety, PhD

• Jennifer Waters, PhD

Physical Therapy

• Andrew Warmuth, DPT

• Eva Frank, PT

Research / Quality Improvement / Lean

• Andrea Postier

• Donna Eull, RN

• Christian Weidner, BS

• Lexie Goertzen

• Laurie Foster

• Jule Yang

Palliative Nursing

• Sarah Hasse, RN

• Michael McLoone

Social Work

• Martha Schermer, LiCSW

• Cyndee Daughtree

• Jessica Convey

• Chaplain: Hal Weiden

• Child Life: Margaret Monsoon

• Music Therapy: Mark Burnet

• Clinic nurse: Blanche Amar

Massage

• Candace Linaris

• Jill Maltrud

• Laura Beck

Admin Assistants

• Katie McQuire

• Cheryl Puumala

Clinic staff

• Brock Hebert

• Allison McQuade

Manager

• Tracey Crocoll

• Liz Leighton, RN

Further Links• The New York Times (Dec 16, 2015) essay by Dr. Stefan Friedrichsdorf “When a Baby Dies” http://

opinionator.blogs.nytimes.com/2015/12/16/when-a-baby-dies/?_r=1

• Video: Kiran Stordalen and Horst Rechelbacher Pediatric Pain, Palliative and Integrative Medicine Clinic Tour https://vimeo.com/122654881

• “Children’s Comfort Promise: Doing everything possible to treat and prevent pain.” Eliminating Needle Pain in children (Feb 2015) Staff video: http://vimeo.com/106286508

• Short Movie: Meet the Interdisciplinary Chronic Pain Clinic Team at Children’s Minnesota: LittleStars TV https://www.youtube.com/watch?t=13&v=Bb1fHxfjdWI

• Video: Tour of the Kiran Stordalen and Horst Rechelbacher Pediatric Pain, Palliative and Integrative Medicine Clinic at Children's Hospitals and Clinics of Minnesota and an overview of the three programs that are offered at Children's under this clinic. https://vimeo.com/123357296

• Short Movie: LittleStarsFilm 'Kali's Story - Beyond the NICU': This amazing pediatric palliative care short movie (7 min) features 8-year-old Kali's journey at Children's Hospitals and Clinics of Minnesota from NICU to today, receiving care by the Pain & Palliative & Integrative Medicine program while inpatient, in the clinic, and at home (Jan 22, 2015) http://www.littlestars.tv/short-films/beyond-the-nicu

Twitter: @NoNeedlessPain

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 Minnesota2525 Chicago Ave S | Minneapolis, MN 55404 | USA

612.813.6450 phone | 612.813.7199 fax

[email protected]://www.childrensmn.org/painpalliativeintegrativemed

Further Training

10th Annual Pediatric Pain Master Class • Minneapolis, Minnesota, USA | June 17-23, 2017

Education in Palliative & End-of-life Care [EPEC]: Become an EPEC-Pediatrics Trainer • Montréal, Québec, Canada | April 29-30, 2017 (Professional Development Workshop: 04/28/17)

Contact: [email protected]

Blog: http://NoNeedlessPain.org

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