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DysFUNctionalPain

CHRIS COOK PHARM.D.CHRISTOPHERCOOK@YVMH.ORG

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

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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

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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