Advanced Pain Management in Pediatric Palliative Care - Multimodal Analgesia Beyond Opioids

Transcription

1 Advanced Pain Management in Pediatric Palliative Care - Multimodal Analgesia Beyond Opioids 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 Stefan.Friedrichsdorf@ChildrensMN.org

2 Appreciate high prevalence of distinct pain pathologies in patients with serious illnesses Define neuropathic pain and describe main causes Develop a step-by-step treatment approach for advanced pain management pain in children with serious illnesses

3 Neuropathic Pain Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system (IASP 2008) Grading System: (1) Definite, (2) Probable; (3) Possible ( but, not all lesions in the somatosensory system lead to neuropathic pain)

4 Prevalence Population prevalence of pain with neuropathic characteristics is likely 6.9% - 10% van Hecke, O., et al., Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain, (4): p Prevalence of neuropathic pain in children unclear Cancer pain > 12 years: Metaanalysis (n=22): Conservative 19%; liberal estimate: 39% Bennett MI, Rayment C, Hjermstad M, Aass N, Caraceni A, Kaasa S. Prevalence and aetiology of neuropathic pain in cancer patients: a systematic review. Pain Feb;153(2): Probably not in infants...? Rats not before P7 to P21, i.e. 4-5 months in children... Damage early on: no memory...adaptive immune system...?

5 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: 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

6 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

7 Neuropathic Pain Assessment Currently there are no validated neuropathic pain scales for children < 18 years Pain Quality Assessment Scale (PQAS) - 20 items Adults NPS Neuropathic Pain Scale - t_03_serv_dist_cduse_pqas.htm Jensen, M.P. (in press). Pain assessment in clinical trials. In D. Carr & H. Wittink (Eds.), Evidence, outcomes, and quality of life in pain treatment. Amsterdam: Elsevier. 12 items t_03_serv_dist_cduse_nps.htm Galer BS, Jensen MP. Development and preliminary validation of a pain measure specific to neuropathic pain: the Neuropathic Pain Scale. Neurology Feb;48(2):332-8

8 Neuropathic Pain Assessment Patients simultaneously may experience different qualities, including Nociceptive Pain Somatic Pain Visceral Pain Psycho-social-spiritual Pain ( Total Pain ) and/or Neuropathic Pain Be creative when measuring pain: a single pain score often will not be enough:

9 Case Report: Clark 15-year-old, relapsed T-cell lymphoma, weight: 72 kgs Onset of chemotherapy-induced bi-pedal neuropathy VAS 9/10 Abdominal pain (hemorrhagic cystitis) Unresponsiveness versus over sedation Autonomic changes at feet

10 WHO Principle: Using a Two-Step Strategy WHO Step 1 Mild Pain Ibuprofen and/or Acetaminophen (Paracetamol) Other NSAIDs? Cox-2 Inhibitor?

11 Nociceptive Pathways & Primary Sites of Action of Analgesics Aδ or C fiber Injury

12 Nociceptive Pathways & Primary Sites of Action of Analgesics Thalamus 2nd Neuron Aδ or C fiber Injury Acetaminophen (Paracetamol) NSAIDs

13 NSAIDs for Neuropathic Pain 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 antiinflammatory 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

14 WHO Principle: Using a Two-Step Strategy WHO Step 1 Mild Pain Ibuprofen and/or Acetaminophen (Paracetamol) Other NSAIDs? Cox-2 Inhibitor? WHO Step 2 Moderate to Severe Pain Morphine or fentanyl, hydromorphone, oxycodone, methadone

15 Opioids for Neuropathic Pain Adult Evidence: Metaanalysis: Opioids, including tramadol, have a consistent efficacy in neuropathic pain Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain Sep;150(3): Multi-mechanism agent Tramadol: RCTs: polyneuropathy and post-amputation pain Hollingshead, Cochrane Database Syst Rev 2005, Sindrup, Pain 1999, 83:85-90; Wilder-Smith, Anesthesiology 2005,103: Strong opioids: RCTs: efficacious for neuropathic pain (NP), including phantom limb pain, chronic peripheral and central NP Huse, Pain 2001,90:47-55; Morley Palliat Med 2003, 17:576-87; Rowbotham N Eng J Med 2003, 384: ; Eisenberg E, McNicol E, Carr DB. Opioids for neuropathic pain. Cochrane Database Syst Rev Jul 19;3:CD

16 Case Example: Multimodal (Opioid-sparing) Analgesia Non-Opioids Acetaminophen / Paracetamol NSAIDs Opioids Tramadol ( weak ) Morphine ( strong ) COX-2-INHIBITOR: Celecoxib 200 mg BID OPIOID: Hydromorphone PCA 1.35 mg/hr (max. 52 boluses/day [1.35mg]) WHO-Principles By the clock By the child By the appropriate route By the WHO ladder Rotation: Methadone 30 mg/day [5 mg IV Q4h -> 10 mg IV Q8h] plus Hydromorphone PCA bolus 2mg IV, lockout 10 minutes PO 10 mg TID -> 12.5 mg TID

17 Nociceptive Pathways & Primary Sites of Action of Analgesics Thalamus Opioids Pre-synaptic nerve terminal â Neurotransmitter release Post-synaptic nerve terminal: Membrane hyperpolarization 2nd Neuron => suppress neuronal excitability Aδ or C fiber Opioids Injury Acetaminophen (Paracetamol) NSAIDs

18 Case Example: Multimodal (Opioid-sparing) Analgesia Non-Opioids Acetaminophen / Paracetamol NSAIDs Opioids Tramadol? ( weak ) Morphine ( strong ) WHO-Principles By the clock By the child By the appropriate route By the WHO ladder Integrative Therapies Massage Heat/cold Deep Breathing Biofeedback Hypnosis etc.

19 Integrative, rehabilitative & supportive therapies Expected part of treatment protocol; Age-appropriate modalities include Acupressure, acupuncture, aromatherapy Physical (massage, TENS, comfort positioning, allowing family for close contact/touch) Rehabilitation (physical therapy, occupational therapy) Behavioral (deep breathing, imagery, hypnosis, smartphone/tablet apps )

20 Case Report: Clark Integrative & supportive therapies Behavioral Therapies Breathing Imagery TENS Physical Therapy Stockings Make-a-wish Hypnosis Individual Psychotherapy Physical Modalities

21 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. Aδ or C fiber Opioids Injury Acetaminophen (Paracetamol) NSAIDs

22 Case Example: Multimodal (Opioid-sparing) Analgesia Non-Opioids Acetaminophen / Paracetamol NSAIDs Opioids Tramadol? ( weak ) Morphine ( strong ) Adjuvants Alpha-Agonist Anticonvulsants TCA/Antidepressants NMDA-receptor-channel blockers Na-receptor-channel blockers Antispasmodics Benzodiazepines Corticosteroids Muscle relaxants Radiopharmaceuticals Bisphosphonates etc. WHO-Principles By the clock By the child By the appropriate route By the WHO ladder Integrative Therapies Massage Heat/cold Deep Breathing Biofeedback Hypnosis etc.

23 Neuropathic Pain Mechanisms Thalamus Periaqueductal grey Central Sensitization: Activities in C-Fibers drives changes in 2nd neuron Descending Inhibition 2nd Neuron Glial activation & cytokine release also involved? Result: á excitability and synaptic efficiency + + Aδ or C fiber Injury induced accumulation of Na-channels => ectopic firing Reduced inhibition in Dorsal Horn Altered Synaptic Transmission: Ca-channel [α-2-δ dysfunction?) + + Injury Peripheral Sensitization: Response to Tissue Injury

24 Role of Cannabis? San Diego, CA

25 Case Report: Clark (1) TRICYCLIC ANTIDEPRESSANT Amitriptyline 25 mg -> 50 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

26 Tricyclic antidepressants (TCA) 61 RCTs (20 antidepressants): TCAs are effective; NNT of 3.6 (for the achievement of at least moderate pain relief). Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev Oct 17;(4):CD 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 Dec;51(6): 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): No effect in chemotherapyinduced neuropathy (pain not primary outcome) Hammack JE, Michalak JC, Loprinzi CL, Sloan JA, Novotny PJ, Soori GS, et al. Phase III evaluation of nortriptyline for alleviation of symptoms of cisplatinum-induced peripheral neuropathy. Pain Jul;98(1-2): Kautio AL, Haanpaa M, Saarto T, Kalso E. Amitriptyline in the treatment of chemotherapy-induced neuropathic symptoms. Journal of Pain and Symptom Management Jan;35(1):31-9. Secondary amine TCAs (e.g. nortriptyline) better tolerated than tertiary amine TCAs (e.g. amitriptyline) with comparable analgesic efficacy Max, N Eng J Med 1992,326:1250-6; Rowbotham, J Pain 2005,6:741-6; Watson, Neurology 1998,51:

27 Amitriptyline Dosage: initial 0.1 mg /kg -> titrate to 0.4 mg/kg p.o., [max mg] (usually not up to 1-2 mg/kg/day) once at night - wean: decrease gradually! Effect: days - weeks; depends on length of symptoms Adverse effects: arrhythmia: EKG (QTc, WPW?), anticholinergic / antihistamine (dry mouth, constipation, blurred vision, sedation) Desipramine: anecdotal evidence of sudden death in children Amitai Y, Frischer H: Excess fatality from desipramine in children and adolescents. J Am Acad Child Adolesc Psychiatry (1):54-60

28 Nociceptive Pathways & Primary Sites of Action of Analgesics Thalamus Periaqueductal grey (endorphins) Integrative (non-pharmacological) therapies Descending Inhibition + 2nd Neuron TCA SSRIs Methadone Tramadol Aδ or C fiber Opioids Injury Acetaminophen (Paracetamol) Tricyclic Antidepressants: (+) Opioid analgesia via serotoninergic mechanism at brainstem NSAIDs

29 Gabapentinoids: Ca-channel α2-δ ligands Voltage-gated Ca-channel G α2-δ subunit [dysfunction?/upregulation role in neuropathic pain] Presynaptic nerve terminal Postsynaptic nerve terminal Glutamate Substance P

30 Gabapentinoids Gabapentin: 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 Jul 20;(3):CD % improved compared to 19% on placebo NNT for effective pain relief in diabetic neuropathy 2.9; post herpetic neuralgia 3.9 Pregabalin: Effective in post herpetic neuralgia, painful diabetic polyneuropathy, central neuropathic pain (19 studies, 7003 participants): effective 300 mg-600 mg daily (at 150 mg daily was generally ineffective). Moore RA, Straube S, Wiffen PJ, Derry S, McQuay HJ. Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev Jul 8; (3):CD No overall evidence for superior efficacy for either of these drugs in neuropathic pain, although lower cost may favor gabapentin Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain Sep;150(3):

31 Nociceptive Pathways & Primary Sites of Action of Analgesics Thalamus Periaqueductal grey (endorphins) Integrative (non-pharmacological) therapies Descending Inhibition + 2nd Neuron TCA SSRIs Methadone Tramadol Combination: Amitriptyline & Gabapentin Aδ or C fiber Injury Inhibitors of excitatory glutamate systems: Gabapentin/Pregabalin Carbamazepine* Valproate Opioids Acetaminophen (Paracetamol) NSAIDs

32 Sodium Channel Blocker: Topical Lidocaine Lidocaine (systemic or local): Decrease of neuropathic pain related to decrease of ectopic ongoing activity in injured afferent nerve fibers Kirillova I, Teliban A, Gorodetskaya N, Grossmann L, Bartsch F, Rausch VH, et al. Effect of local and intravenous lidocaine on ongoing activity in injured afferent nerve fibers. Pain Jul;152(7): Topical Lidocaine 5% patch (Lidoderm, generic available). Metaanalysis: Data is conflicting Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain Sep;150(3): Oral mexiletine, tocainide, flecainide are analgesic in neuropathic pain: High side effect liability from oral drugs; generally considered third-line (1) Oskarsson P et al, Diabetes Care, 1997;20: Challapalli et al, Cochrane Database Sys Rev. 2005;CD (2) Portenoy R: The Annual Assembly of American Academy of Hospice and Palliative Medicine, Austin, TX, 2009 (3) Ferrante FM, Paggioli J, Cherukuri S, Arthur GR. The analgesic response to intravenous lidocaine in the treatment of neuropathic pain. Anesthesia and analgesia.1996 Jan;82(1): Efficacy of IV lidocaine supported by RCTs

33 Opioid induced tolerance and hyperalgesia Opioid mu-receptor uncoupling Gi/o proteins stimulation Genes activation Protein Kinase-C Inhibition of Ca channels: â neurotransmitter release Alter response characteristics of neuron => Suppress neuronal excitability Membrane Hyperpolarization (K+ channel) generation Other neuromodulators

34 Opioid induced tolerance and hyperalgesia Opioid mu-receptor Gi/o proteins activation Proteine Kinase-C activation Chen L, Nature 1992; 365:521-3 NMDA-receptor

35 NMDA-Receptor Channel Blocker Glutamate recognition site Na + Ca 2+ Glycine recognition site Cell membrane Mg 2+ K + 1. Membrane potential at resting level! -> channel blocked by Magnesium Excitatory NMDA (N-Methyl-d-Aspartat) Receptor channel complex

36 NMDA-Receptor Channel Blocker Glutamate recognition site Na + Ca 2+ Glycine recognition site Cell membrane K + 2. Membrane potential changed as a result of á excitation â Opioid-sensitivity $ - Central (dorsal horn) sensitization - radiation of pain - spontaneous pain - Hyperalgesia, allodynia

37 NMDA-Receptor Channel Blocker Glutamate recognition site Na + Ca 2+ Glycine recognition site Cell membrane Ketamine K + 3. Phencyclidin (PCP) - binding sites [uncompetitive NMDA receptor antagonists with moderate affinity] - Ketamine - Methadone - Levorphanol - (Dextrometorphane?)

38 Ketamine Sedative-Hypnotic-Dissociative Dosing: 1-2 mg/kg/dose IV Analgesic (subanesthetic) Dosing: IV: 1-5 mcg/kg/min [= mg/kg/hr] Adverse effects: intracranial hypertension, tachycardia, psychotomimetic phenomena (euphoria, dsyphoria, vivid hallucinations) -> at lowdose?? 37 RCTs (n=2240): subanesthetic Ketamine effective in reducing morphine requirements in first 24 hours after surgery, reduces postoperative nausea and vomiting; Adverse effects are mild or absent. Bell RF, et al. Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev Jan 25;(1):CD Metaanalysis: NMDA antagonists (& mexiletine) have no consistent clinical relevant efficacy in neuropathic pain Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain Sep; 150(3):

39 Ketamine Steady-state oral/parenteral ratio unclear Bio-availibilty 93% IM/IV; 20% PO Ketamine -> norketamine Potency ketamine: norketamine 3:1 (anesthetic); 1:1 (analgesic) Plasma half-life: ketamine 1-3 hrs; norketamine 12 hrs Maximum blood concentration of norketamine: oral > IV Domino E, Clinical Pharm Therapeut 1984, 36:645-53; Clements JA, J Pharm Scienc 1982,71: Estimated at 1:1-1:3 (i.e. 1mg IV = 1-3 mg PO) Benitez-Rosario MA, Salinas-Martin A, Gonzalez-Guillermo T, Feria M. A strategy for conversion from subcutaneous to oral ketamine in cancer pain patients: effect of a 1:1 ratio. Journal of Pain and Symptom Management Jun;41(6):

40 Case Report: Clark 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 bolus Day 2: $á 12 mg/hr [2.8 mcg/kg/min] plus 12 mg bolus Day 3:$á 16 mg/hr [3.7 mcg/kg/min] plus 16 mg bolus Day 5: $á 24 mg/hr [5.6 mcg/kg/min] plus 16 mg bolus Day 8: $ Day 10: $ Day 14: $ Change to 40 mg PO PRN 40 mg PO TID [plus 40 mg PRN] Discontinued [changed to PRN only] Absent benzodiazepine -> no psychotropic adverse effects

41 Case Report: Clark Number of Hydromorphone PCA Boluses 55 -> 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 Pain â â â Function á á

42 Case Report: Clark at Home 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: 50 mg QHS Ketamine: 40 mg PO PRN Q1h ( discontinued after 2 weeks) Lidocaine Patches: Discontinued after 3 weeks

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44 Other Adjuvant Analgesics / Coanalgesics α-adrenergic Agonists (Dexmedetomidine; clonidine) Postsynaptic alpha-2- adrenergic & mu-opioid receptors activate the same K-channel via inhibitory Gi/ 0 -proteins Benzodiazepines: gammaaminobutyric acid (GABA) receptors Capsaicin: 2 Metaanalyses Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain Sep;150(3): Mou, J., et al., Efficacy of Qutenza(R) (capsaicin) 8% patch for neuropathic pain: a meta-analysis of the Qutenza Clinical Trials Database. Pain, (9): p decrease postoperative opioid consumption, pain intensity, and nausea. Recovery times are not prolonged. Blaudszun G, Lysakowski C, Elia N, Tramer MR. Effect of Perioperative Systemic alpha2 Agonists on Postoperative Morphine Consumption and Pain Intensity: Systematic Review and Meta-analysis of Randomized Controlled Trials. Anesthesiology Jun; 116(6): Sensory- Selective (Nociceptive- Selective) Nerve Blockade Schumacher MA, Eilers H. TRPV1 splice variants: structure and function. Front Biosci. 2010;15: Binshtok AM, Bean BP, Woolf CJ. Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature Oct 4;449(7162):

45 Nociceptive Pathways & Primary Sites of Action of Analgesics Thalamus Periaqueductal grey (endorphins) Integrative (non-pharmacological) therapies Descending Inhibition + 2nd Neuron TCA SSRIs Methadone Tramadol Stimulation of inhibiting GABA system Baclofen Benzodiazepines Valproate Aδ or C fiber Inhibitors of excitatory glutamate systems: Gabapentin/Pregabalin Carbamazepine* Valproate NMDA-Channel Blockers Ketamine Methadone Opioids Acetaminophen (Paracetamol) NSAIDs Injury Sodium-channel blockade carbamazepine* lidocaine

46 Case Example: Multimodal (Opioid-sparing) Analgesia Non-Opioids Acetaminophen / Paracetamol NSAIDs Opioids Tramadol? ( weak ) Morphine ( strong ) Adjuvants Alpha-Agonist Anticonvulsants TCA/Antidepressants NMDA-receptor-channel blockers Na-receptor-channel blockers Antispasmodics Benzodiazepines Corticosteroids Muscle relaxants Radiopharmaceuticals Bisphosphonates etc. WHO-Principles By the clock By the child By the appropriate route By the WHO ladder Integrative Therapies Massage Heat/cold Deep Breathing Biofeedback Hypnosis etc. Invasive Approaches Regional anesthesia Neuraxial anesthesia - Epidural or intrathecal - Nerve blocks - Neurolytic blocks [Intraventricular opioids?] [Percutaneous cervical cordotomy?]

47 Interventional management of neuropathic pain in adults NeuPSIG recommendations 2013: Due to the paucity of high-quality clinical trials, no strong recommendations can be made. Dworkin, R.H., et al., Interventional management of neuropathic pain: NeuPSIG recommendations. Pain, (11): p (2) steroid injections for radiculopathy (3) spinal cord stimulation (SCS) for failed back surgery syndrome 4 weak recommendations based on the amount and consistency of evidence, including degree of efficacy and safety, are: (4) SCS for CRPS type 1 (who do not respond adequately to noninvasive treatments and sympathetic nerve blocks) (1) epidural injections for herpes zoster Based on the available data, we recommend not to use sympathetic blocks for PHN nor radiofrequency lesions for radiculopathy

48 Regional anesthesia approaches to pain management in PPC Review of current 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, (6): p central neuraxial infusions peripheral nerve and plexus blocks or infusions neurolytic blocks implanted intrathecal ports & pumps for baclofen, opioids, local anesthetics, and other adjuvants

49 Adult Evidence Based Recommendations Neuropathic Pain First Line Tricyclic antidepressants & other dual reuptake inhibitors of both serotonin and norepinephrine Ca-channel α2-δ ligands Select clinical circumstances: Opioids including tramadol Second Line Some circumstances: certain antiepileptic and antidepressants, mexiletine, NMDA-receptor antagonists, topical capsaicin Third Line Certain antiepileptic and antidepressants, mexiletine, NMDA-receptor antagonists, topical capsaicin Dwokin et al. Pain 2007, 132: Opioids including tramadol

50 Management of Neuropathic Pain in Pediatric Palliative Care: Suggested Non-Evidence-based Step-by-Step Approach (2) Integrative therapies; manage comorbidities (anxiety, sleep disturbances) (1) Identify and treat underlying disease process (radiation?) (corticosteroids?)

51 Management of Neuropathic Pain in Pediatric Palliative Care: Suggested Non-Evidence-based Step-by-Step Approach (8) Regional anesthesia (7) NMDA-receptor-channel blocker [benzodiazepine? α- agonist? IV lidocaine?] (6) Lidocain patch (if localized pain) (5) Tricyclic Antidepressant and Ca-channel α2-δ ligand (4) Tricyclic Antidepressant (or Ca-channel α2-δ ligand) ± ketamine (3) Opioid (plus non-opioid) analgesics [consider Tramadol or Methadone] (2) Integrative therapies; manage comorbidities (anxiety, sleep disturbances) (1) Identify and treat underlying disease process (radiation?) (corticosteroids?)

52 Conclusions Neuropathic pain often underassessed and under-treated Treat underlying cause, if possible and appropriate Low-dose Ketamine may represent a potent adjuvant analgesia Careful step-by-step approach (combining integrative, rehabilitative, pharmacological and interventional therapies) warranted First Line medications: Opioids (?), Amitriptyline, Gabapentin

53 Further Training Education in Palliative & End-of-life Care [EPEC]: Become an EPEC- Pediatrics Trainer Phoenix, AZ May 4-5, th Annual Pediatric Pain Master Class Minneapolis, MN June 20-26, 2015 Blog: Stefan J. Friedrichsdorf, MD, FAAP Associate Professor of Pediatrics, University of Minnesota Medical Director, Department of Pain Medicine, Palliative Care & Integrative Medicine Children's Hospitals and Clinics of Minnesota 2525 Chicago Ave S Minneapolis, MN USA phone fax stefan.friedrichsdorf@childrensmn.org painpalliativeintegrativemed