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5/19/2016
1
DysFUNctionalPain
CHRIS COOK [email protected]
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.
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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
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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 myelinationDull-Aching poorly
localized pain
Transmission
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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/5HT3
GABA
Neurotensin
Receptors µ = Mu
Mu1= desired effects
Mu2 = undesirable effects
ĸ = Kappa Desirable and
undesirable effects
δ = Delta & ơ = Sigma
NMDA antagonism
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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++
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IASP NeuPSIG
1st line = TCA’s, SNRI’s, Ca++ channel α2-δ ligand
TCA’s 1st line unless significant cardiac history
Duloxetine 1st line for Peripheral Diabetic Neuropathy
Lidocaine topical for patients with well localized pain
Presentation with severe pain should begin with opioids
IASP NeuPSIG
2nd line = Tramadol
Opioid combinations w/APAP
3rd 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
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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
1st line = Gabapentin/pregabalin, TCA’s, SNRI (duloxetine, venlafaxine)
2nd line = Tramadol, acetaminophen, combined 3rd line = Strong opioids
HIV associated polyneuropathy – Lamotrigine (if on antiretrovirals), smoking cannabis, capsaicin
Postherpetic Neuralgia
1st line = TCA, gabapentin/pregabalin, lidocaine
2nd line = Capsaicin, strong opioids
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Trigeminal Neuralgia
Oxcarbazepine, carbamazepine
Patients with intolerable side effects from 1st line therapy Lamotrigine
Surgery
Central Neuropathic Pain
1st line = Gabapentin/pregabalin, amitriptyline 2nd 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
http://m.youtube.com/watch?v=cP4zgb9H3Cg&desktop_uri=%2Fwatch%3Fv%3DcP4zgb9H3cg
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Tricyclic Antidepressants
Mechanism of Action 5HT3, 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
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SNRI (duloxetine, venlafaxine)
Mechanism of Action
Inhibits the reuptake of serotonin and norepinephrine back into the presynaptic neuron in the descending inhibitory neuropathway
Side Effects
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 α2-δmodulating the release of excitatory neurotransmitters
D. Bind BZD receptor on GABAergic neurons causing membrane stabilization and decreased action potential
Ca++ Channel α2-δ Ligand
MOA: Binds to voltage gated Ca++ channel α2-δ, this is a presynaptic channel that modulates the release of excitatory neurotransmitters which participate in nociception
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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
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Lamotrigine
Mechanism of action Inhibition of the release
of glutamate and voltage gated Na+
channels
Kinetics 98% bioavailable, t½
=24-48hr,
Side effects Extra emphasis on
serious skin reaction, GI side effects and vision changes
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
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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
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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
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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
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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 5HT3 and NE
Methadone Absorption
Bioavailability - highly variable 40-100%
Tmax 1 to 7.5hours
85 – 90% protein bound
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Methadone Distribution
Methadone is highly lipophilic Lipophilicity causes redistribution into fat
http://www.google.com/imgres?imgurl=http://images.sciencedaily.com/2007/12/071210163211-large.jpg&imgrefurl=http://www.sciencedaily.com/releases/2007/12/071210163211.htm&usg=__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 12-150 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
http://www.edrep.org/media/misc/HappyKidneyRededren1.jpg
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Methadone Kinetics
t½ = 24hr (average) Steady state not achieved until
70-120hr
Accumulation occurs in 5-10 days
Note ratio only represents chronic methadone use
Oral Morphine Dose
Morphine : Methadoneratio
<100 mg 3:1
101-300 mg 5:1
301-600 mg 10:1
601-800 mg 12:1
801-1000 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
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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
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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 5HT3
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
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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
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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;9:166-174. 2. http://www.cdc.gov/nchs/hus.htm. 3. Blay SL, Andreoli SB, Gastal FL. Chronic painful physical conditions, disturbed sleep and psychiatric morbidity: results from an elderly survey. Ann ClinPsychiatry. 2007;19:169-174. 4. Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. 2011. 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;8158-165. 6. Von Korff M, Lin EH, Fenton JJ, Saunders K. Frequency and priority of pain patients’ health care use. Clin J Pain. 2007;23:400-408. 7. 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;290:2443-2454. 8. Centers for Disease Control and Prevention. Vital signs: overdoses of prescription opioid pain relievers --- United States, 1999-2008. MMWR. 2011;60:1486-1492. 9. 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; 1968:423-429. 10. Willis WD. The somatosensory system, with emphasis on structures important for pain. Brain Res Rev. 2007;55:297-313. 11. 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;9:463-484. 14. Jarvis MF, Boyce-Rustay JM. Neuropathic pain: models and mechanisms. CurrPharm Des. 2009;15:1711-1716. 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, 1991:393-416. 16. Truini A, Cruccu G. Pathophysiological mechanisms of neuropathic pain. Neurol Sci. 2006 May;27 Suppl 2:S179-182. 17. Cummins TR, Sheets PL, Waxman SG. The roles of sodium channels in nociception: Implications for mechanisms of pain. Pain. 2007;131:243-257. 18. 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;11:1635-1653 19. Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009;32:1-32. 20. Bingel U, Tracey I. Imaging CNS modulation of pain in humans. Physiology (Bethesda). 2008;23:371-380. 21. Gamsa A. The role of psychological factors in chronic pain. I. A half century of study. Pain. 1994;57:5-15.
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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; 2000:498-503. 23. 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. 2008:122-131. 24. 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; 1996. 25. Portenoy RK, Kanner RM. Definition and assessment of pain. In: Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice. Philadelphia, PA: FA Davis; 1996