DysFUNctional Pain 5/19/2016. Potential conflicts of interest. Objectives

Transcription

1 DysFUNctional Pain CHRIS COOK PHARM.D. Potential conflicts of interest Nothing to disclose Objectives Understand the pathophysiology of neuropathic pain and fibromyalgia Explain multimodal therapy in regards to the treatment of pain Explain the mechanism of action of the types of medications used to treat neuropathic pain and fibromyalgia Be able to determine best fit medications for patient cases based on MOA, side effects, interactions etc. 1

2 Classifications of Pain Type of Pain Acute Post-operative Trauma Chronic Cancer Non-Cancer Source of pain Nociceptive Neuropathic Physiology of Nociception Transduction Transmission Perception Modulation 2

3 Transduction Ion Transfer K + = Potassium Na + = Sodium Ca ++ = Calcium Generate an action potential Inflammatory Soup Transmission Aδ Nerve fibers Large Heavily myelinated Sharp well localized pain C-Afferent fibers Smaller Less myelination Dull-Aching poorly localized pain Transmission 3

4 Perception End result of the neural activity of pain transmission Conscious awareness of pain Requires activation of the higher brain structure Thalamus Limbic System Generate a network of cortical and subcortical gray matter Includes processes that influence movement, emotions, and drives (related to pain) Modulation Neurotransmitters Endogenous Opiates Enkephalins Endorphins Dynorphins Nociceptins (ORL-1) NE/DA/5HT 3 GABA Neurotensin Receptors µ = Mu Mu 1 = desired effects Mu 2 = undesirable effects ĸ = Kappa Desirable and undesirable effects δ = Delta & ơ = Sigma NMDA antagonism 4

5 Definition of Neuropathic Pain Abnormal processing of sensory input by the peripheral or central nervous system Peripheral Mechanisms of Neuropathic Pain Collateral sprouting (also in CNS) Peripheral sensitization by release of substances from damaged cells Alteration in ion channel expression Recruitment of silent nociceptors Lowered threshold for nerve depolarization Central Mechanisms of Neuropathic Pain Prolonged binding of neurotransmitters glutamate & substance P hyperexcitability of central neurons Lowered threshold for nerve conduction Increased response to stimuli (allodynia, hyperalgesia) Enlarged receptor field NMDA receptor activation influx of Ca ++ 5

6 IASP NeuPSIG 1 st line = TCA s, SNRI s, Ca ++ channel α 2 -δ ligand TCA s 1 st line unless significant cardiac history Duloxetine 1 st line for Peripheral Diabetic Neuropathy Lidocaine topical for patients with well localized pain Presentation with severe pain should begin with opioids IASP NeuPSIG 2 nd line = Tramadol Opioid combinations w/apap 3 rd line = Miscellaneous agents Antidepressants not previously mentioned SSRIs (bupropion, citalopram, paroxetine) Carbamazepine for Trigeminal Neuralgia Multimodal Analgesia Using 2 or more classes of medications to treat a painful condition Used to target different pain mechanisms in the PNS and CNS Allows for equal or greater analgesia Lower doses of each agent (in general) Decreased side effects Increased efficacy 6

7 Neuropathic Pain Syndromes Painful Polyneuropathy (PPN) Postherpetic Neuralgia (PHN) Trigeminal Neuralgia (TN) Central Neuropathic Pain (CP) Other Neuropathic Pain Conditions (NP) Painful diabetic neuropathy (PDN) Painful Polyneuropathy 1 st line = Gabapentin/pregabalin, TCA s, SNRI (duloxetine, venlafaxine) 2 nd line = Tramadol, acetaminophen, combined 3 rd line = Strong opioids HIV associated polyneuropathy Lamotrigine (if on antiretrovirals), smoking cannabis, capsaicin Postherpetic Neuralgia 1 st line = TCA, gabapentin/pregabalin, lidocaine 2 nd line = Capsaicin, strong opioids 7

8 Trigeminal Neuralgia Oxcarbazepine, carbamazepine Patients with intolerable side effects from 1 st line therapy Lamotrigine Surgery Central Neuropathic Pain 1 st line = Gabapentin/pregabalin, amitriptyline 2 nd line = Tramadol, strong opioids Lamotrigine Post stroke pain Spinal cord injury with incomplete cord lesion Allodynia Cannabinoids in patients with multiple sclerosis Pain score from a patient point of view ktop_uri=%2fwatch%3fv%3dcp4zgb9h3cg 8

9 Tricyclic Antidepressants Mechanism of Action 5HT 3, NE reuptake inhibitor Anticholinergic-antimuscarinic α1-adrenergic antagonist Antihistamine (H1), Sodium channels inhibition at overdose levels Selective TCA s = imipramine, nortriptyline, amitriptyline Less anticholinergic side effects TCA s Continued Dosing: Start with single low dosages at bedtime titrated as tolerated. Effective doses vary. TCA s have much better efficacy than the SSRI s Tertiary amines are more effective than secondary amines but with a worse side effect profile Tertiary Amitriptylline, imipramine Secondary Desipramine, nortriptyline Pain relief properties are not related to antidepressant properties Common Side Effects of TCA 9

10 SNRI (duloxetine, venlafaxine) Mechanism of Action Side Effects Inhibits the reuptake of serotonin and norepinephrine back into the presynaptic neuron in the descending inhibitory neuropathway GI disturbance, somnolence hyperhidrosis, dizziness (w/discontinuation), rare elevations in plasma glucose and hepatic enzymes HTN Best tolerated = venlafaxine ER>IR>duloxetine Polling Question What is the mechanism of action of gabapentin? A. Binds to the GABA site of GABAergic neurons in the CNS causing inhibitory firing of pain signals in the descending pathway B. Binds to the GABA site of GABAergic neurons in the CNS causing inhibitory firing of pain signals in the ascending pathway C. Binds to voltage gated Ca ++ channel α 2 -δ modulating the release of excitatory neurotransmitters D. Bind BZD receptor on GABAergic neurons causing membrane stabilization and decreased action potential Ca ++ Channel α 2 -δ Ligand MOA: Binds to voltage gated Ca ++ channel α 2 -δ, this is a presynaptic channel that modulates the release of excitatory neurotransmitters which participate in nociception 10

11 Gabapentin Non-linear kinetics 2 saturable absorption F of gabapentin is inversely proportional to the dose secondary to the L-amino transport system Absorption is greatly increased by food t½ increases from average of 6 hours to up to 40 hours in patients with decreased renal function Dosing in neuropathy requires usually 1800mg/day Titration may occur at increases of ~300mg/day Pregabalin In addition to the MOA mentioned above may affect descending serotonergic/noradrenergic pain pathway from brainstem to spinal cord Side Effects >10% Pregabalin Peripheral edema, weight gain Somnolence & dizziness up to >35% Xerostomia, constipation Tremor Gabapentin Ataxia, dizziness, somnolence 11

12 Lamotrigine Mechanism of action Inhibition of the release of glutamate and voltage gated Na + channels Side effects Extra emphasis on serious skin reaction, GI side effects and vision changes Kinetics 98% bioavailable, t½ =24-48hr, All neuropathic and fibromyalgia are off label uses Carbamazepine Mechanism of action Thought to work in the thalamus and possibly affect sodium channels similar to lamotrigine. Side effects Constipation Vomiting Dizziness Capsaicin Mechanism of action Induces the release of substance P until depleted relief until substance P is repleted by the body Side effects Pain Pain Pain Discontinuation rate due to worsening of pain levels 12

13 Lidocaine MOA: Blocks initiation and conduction of nerve impulses Dosing up to 4 patches at a time (mfr = 3) 11hr to peak concentration 1-2 hr. t½ 13

14 Opioids for chronic pain NIH Short-term studies show equivocal evidence reducing neuropathic pain Intermediate-term studies demonstrate significant efficacy of opioids over placebo Reported adverse events of opioids are common but not life threatening Opioids MOA: Opioid receptor agonist decreasing pain impulse transmission at the spinal cord level and higher in the CNS. Also causes peripheral vasodilation by depressing the responsiveness of alpha-adrenergic receptors. Binding to opiate receptors in the periphery causes smooth muscle relaxation 14

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16 Opiate Effects (CNS) Analgesia Direct stimulation of the chemoreceptor trigger zone (CTZ) Decreased responsiveness in respiratory center Opioid effects (periphery) Decreased propulsive contractions of the GI tract Decreased biliary and pancreatic secretions Histamine release causing pruritus Venous vasodilation Opioid Fun Facts Anecdotal case report: 63yo M s/p bowel resection for colorectal cancer receiving Morphine sulfate extended release (GENERIC) Hydromorphone Longer respiratory depressive effect than analgesic effect Lipophilicity Morphine Oxycodone Hydromorphone Methadone Fentanyl 16

17 Tramadol MOA: Tramadol and its metabolite (M1) are centrally acting mu receptor agonists, also inhibits reuptake of serotonin and norepinephrine Onset = 1hr, Duration = 9hr, t½ = ~7hr tramadol, ~8hr M1, Side Effects: Constipation, nausea, pruritus, sedation, dizziness, headache Methadone MOA Synthetic mu opiate receptor agonist Antagonism of NMDA receptor Reuptake inhibitor of 5HT 3 and NE Methadone Absorption Bioavailability - highly variable % Tmax 1 to 7.5hours 85 90% protein bound 17

18 Methadone Distribution Methadone is highly lipophilic Lipophilicity causes redistribution into fat large.jpg&imgrefurl= Br-1L-O6goxN8zOrduezR2ShQKs=&h=399&w=600&sz=17&hl=en&start=21&zoom=1&tbnid=- KoYcPLae9lo2M:&tbnh=90&tbnw=135&ei=gnoXT8OtGujWiAKd6d3fDw&prev=/search%3Fq%3Ddistribution%2Bof%2Bfat%26um%3D1%26hl%3Den%26sa%3DN%26gbv%3D2%26tbm%3Disch& Methadone Metabolism Duration of action increases with increased dosing T½ of up to hours Analgesic action is shorter than t½ Metabolism is ALWAYS variable 3A4, 1A2, 2D6 Methadone Elimination Methadone is eliminated almost completely in the feces Very long elimination phase 18

19 Methadone Kinetics t½ = 24hr (average) Steady state not achieved until hr Accumulation occurs in 5-10 days Oral Morphine Dose <100 mg 3: mg 5: mg 10:1 Morphine : Methadone ratio Note ratio only represents chronic methadone use mg 12: mg 15:1 >1000 mg 20:1 Methadone Side Effects Less constipation than other opiates Sedation Respiratory depression QT prolongation Ketamine Mechanism of action NMDA receptor antagonist Analgesic Psychomimetic Opioid sparing effect through Attenuation of the occurrence of opioid dependence Reduces opioid withdrawl Side effects Cardiovascular Arrythmia (brady/tachycardia) Hyper/Hypotension Rash Anorexia/nausea/salivation Emergence reactions Vivid dreams Hallucinations/delirium 10 to 20% of patients at anesthetic doses 19

20 Topic Discussion Pharmacist role in pain management Restriction of hydromorphone on formularies Use of Exparel Students who look at these in advance can bring up some topic discussion! Fibromyalgia Epidemiology Affects 2 10% of the general population, in all ages, ethnic groups, and cultures Its gender distribution is up to seven times more common in females than males 15% of patients receive disability funding Fibromyalgia Chronic widespread pain for which no alternative cause can be identified (diagnosis of exclusion) Rheumatologic syndrome characterized by chronic, diffuse musculoskeletal pain and tenderness sleep disturbances fatigue affective dysfunction 20

21 Fibromyalgia Pathophysiology Neuroendocrine: Dysfunction of the hypothalamic-pituitary-adrenal axis Blunted cortisol response Abnormal growth hormone regulation Stage 4 sleep disruption Neurotransmitter: Elevated levels of Tryptophan in CNS but decreased 5HT 3 Elevated levels of substance P in the CSF Elevated levels of nerve growth factor in the CSF Fibromyalgia pathophysiology Neurosensory: Central amplification of pain and/or reduced antinociception Genetic: polymorphisms of genes in the catacholaminergic systems Trauma: 22% of patients get fibromyalgia symptoms after a whiplash accident Fibromyalgia Treatment Goal is NOT resolution of symptoms Significant improvement can be obtained with adequate therapy MANAGEMENT is multimodal Self care Psychological/psychiatric support Physical therapy +/- TENS Pharmacologic treatment 21

22 Pharmacology for Fibromyalgia Low-dose tricyclic antidepressants (amitriptyline) Dual serotonin-norepinephrine reuptake inhibitors Antiepileptic (gabapentin, pregabalin) Selective serotonin reuptake inhibitors Fibromyalgia Treatment in a nutshell Naltrexone Opioid antagonist Best evidence for pain treatment is at low doses reducing pain intensity and improving mood. Low side effect profile. Should never be co-administered with opioids The primary mechanism of low-dose naltrexone is thought to be immune modulation Also has some evidence in hyperalgesia 22

23 Questions 1. Watkins EA, Wollan PC, Melton LJ 3rd, Yawn BP. A population in pain: report from the Olmsted County health study. Pain Med. 2008;9: Blay SL, Andreoli SB, Gastal FL. Chronic painful physical conditions, disturbed sleep and psychiatric morbidity: results from an elderly survey. Ann Clin Psychiatry. 2007;19: Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research Washington, DC. The National Academies Press. 5. Sawyer P, Lillis JP, Bodner EV, Allman RM. Substantial daily pain among nursing home residents. J Am Med Directors Assoc. 2007; Von Korff M, Lin EH, Fenton JJ, Saunders K. Frequency and priority of pain patients health care use. Clin J Pain. 2007;23: Stewart WF, Ricci JA, Chee E, Morganstein D, Lipton R. Lost productive time and cost due to common pain conditions in the US workforce. JAMA. 2003;290: Centers for Disease Control and Prevention. Vital signs: overdoses of prescription opioid pain relievers --- United States, MMWR. 2011;60: Melzack R, Casey KL. Sensory, motivational, and central control determinants of pain: A new conceptual model. In: Kenshalo D, ed. The Skin Senses. Springfield, IL: Charles C. Thomas; 1968: Willis WD. The somatosensory system, with emphasis on structures important for pain. Brain Res Rev. 2007;55: Stein C, Clark JD, Oh U, et al. RH. Peripheral mechanisms of pain and 13. Apkarian AV, Bushnell MC, Treede RD, Zubieta JK. Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain. 2005;9: Jarvis MF, Boyce-Rustay JM. Neuropathic pain: models and mechanisms. Curr Pharm Des. 2009;15: Portenoy RK. Issues in the management of neuropathic pain. In: Basbaum AI, Besson J-M, eds. Towards a New Pharmacotherapy of Pain. Chichester, UK: John Wiley & Sons, 1991: Truini A, Cruccu G. Pathophysiological mechanisms of neuropathic pain. Neurol Sci May;27 Suppl 2:S Cummins TR, Sheets PL, Waxman SG. The roles of sodium channels in nociception: Implications for mechanisms of pain. Pain. 2007;131: Dickinson BD, Head CA, Gitlow S, Osbahr A. Maldynia: Pathophysiology and Management of Neuropathic and Maladaptive Pain A Report of the AMA Council on Science and Public Health Pain Med. 2010;11: Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009;32: Bingel U, Tracey I. Imaging CNS modulation of pain in humans. Physiology (Bethesda). 2008;23: Gamsa A. The role of psychological factors in chronic pain. I. A half century of study. Pain. 1994;57:

24 22. Pain Disorder. In: Frances A, Pincus HA, First MB, et al, eds. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 2000: Lebovitz A. The psychological assessment of pain in patients with chronic pain. In Wilson PR, Watson PJ, Haythornwaite, Jensen TS, eds. Chronic Pain (Clinical Pain Management, 2nd Edition). London: Hodder and Stoughton Ltd. 2008: Donohoe CD. Evaluation of the Patient in Pain-Targeted History and Physical Examination. In: Waldman SD, Winnie AP, eds. Interventional Pain Management. Philadelphia, PA: WB Saunders; Portenoy RK, Kanner RM. Definition and assessment of pain. In: Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice. Philadelphia, PA: FA Davis;