Neuropathic Pain Neuropathic Pain 2.2

Objectives

Pharmacologic At the conclusion of this presentation, Management of pharmacists will be able to: 1.1. Differentiate between nociceptive and Neuropathic Pain neuropathic pain 2.2. Identify classes of drugs commonly used to treat neuropathic pain Joseph R. Ineck, Pharm.D.,Pharm.D ., CPE Pharmacist: St. Luke’s Health System 3.3. Correlate pharmacologic actions of medications to sites of action within the nervous system (rational polypharmacy))polypharmacy

Nociceptive Pain Types of Pain Examples

Nociceptive (somatic or visceral) Rheumatoid or osteoarthritis dull, aching, well localized or referred Myofascial pain to distant sites Fibromyalgia Neuropathic Ischemic disorders sharp, burning, shooting, stabbing, Chronic back pain tingling, hot, cold, numb Ulcerative colitis, etc.

1 Pain Signaling Neuropathic Pain

Distinctly different from nociceptive pain Sustained by abnormal processing of sensory input by the peripheral or central nervous system Vast number of pain syndromes exist Often difficult to treat Relief may not be complete Drugs have “incomplete” efficacy and dosedose-- limiting side effects

Neuropathic Pain Peripherally Generated Examples Neuropathic Pain

Trigeminal neuralgia painful polyneuropathies: pain felt PostPost--herpeticherpetic neuralgia along the distribution of diffuse peripheral nerves PostPost--strokestroke pain painful mononeuropathies: associated Phantom pain with peripheral nerve injury, pain felt Diabetic neuropathy pain along the distribution of the damaged nerve

2 Manifestations of Neuropathic Pain: Neuropathic Pain Stimulus Independant

Stimulus Independent Constant, burning dysethetic ** pain ––persistentpersistent or paroxysmal ––oftenoften associated with aching or cramp--likecramp like pain in deep tissue ––shooting,shooting, lancinating, burning, tingling, ––sometimessometimes described as if the involved area aching, or crampcramp--likelike pain in deep tissue were “on fire” Stimulus Evoked May be severe pressurepressure--likelike sensation, as if ––hyperalgesiahyperalgesia the involved limb were about to explode ––allodyniaallodynia **impairment of sensation, disagreeable sensation

Neuropathic Pain: Neuropathic Pain: Stimulus Independant Stimulus Evoked

Paroxysmal pain Allodynia: perception of pain in response to ––usuallyusually fleeting and intense, shock--likeshock like or what is normally an innocuous stimulus: lancinating ––contactcontact of clothing or gentle breeze across skin: unbearable pain ––cancan be spontaneous or evoked by ––perceptionperception of ice as intense heat movement or tactile stimulation Hyperalgesia: exaggerated response to physical stimuli ––intenselyintensely painful response to modest irritation such as pinprick

3 Neuropathic Pain: Underlying Etiology: Sympathetic Involvement Peripherally Generated NP

CRPS: evidence of autonomic Metabolic disorders: diabetes, renal failure, instability alcohol abuse, niacin deficiencies ––involvedinvolved limb swells, abnormal sweating Infectious or postinfectious causes: HIV, Lyme disease, postherpetic neuralgia ––changeschanges in skin, nails, bones Toxin induced: heavy metals (arsenic), vincristine, cisplatin Immune mediated: vasculitis Inherited disorders

Underlying Etiology : Centrally Generated NP Centrally Generated NP Examples

Caused by a lesion or dysfunction in Vascular lesions in brain and spinal cord the CNS Multiple sclerosis Traumatic spinal cord injury ––OneOne theory is that pain is the result of Tumors activity produced by an irritable focus Abscesses created at the site of injury, an ectopic Inflammatory diseases: myelitis caused by focus viruses, syphilis Epilepsy Parkinson’s disease

4 Manifestation & Physiology Neuropathic Pain: of Neuropathic Pains ectopic activity

Possible Mechanisms of Neuropathic Pain: –– Peripheral sensitization –– Ectopic foci of hyperexcitability in neuron –– Sympathetic maintained activity –– Loss of inhibition of dorsal horn neuron –– Central sensitization –– Rewiring of synaptic connection in the dorsal horn –– Phenotypic switch

Woolf CJ, et al. Neuropathic Pain: Aetiology, Symptoms, Mechanisms and Management. Lancet . 1999;353:19591999;353:1959-- 6464

Neuropathic Pain: Central Sensitization ephaptic activity

Central neurons at the level of the spinal cord become hyperexcitable following a peripheral nerve injury ––ThisThis is called central sensitization and contributes to the pain of peripheral neuropathies Transmitters released in the dorsal horn include glutamate and others ––GlutamateGlutamate binds to NMDA receptors ––WindWind--upup phenomenon

5 Neuropathic Pain: Summary: Manifestations, windwind--upup Etiology & Pathophysiology

Diverse sets of diseases No single mechanism for a defined disease state Different pain symptoms from same mechanism Same pain symptoms from different mechanism Multiple overlapping mechanisms possible for pain symptoms Can not predict mechanism based on pain symptoms

Otto M, et al. Pain Phenomena and Possible Mechanisms in Patients with Painful Polyneuropaty. Pain .2003;101:187.2003;101:187--192192

Neuropathic Pain: Management of NP Assessment

Based on underlying pathophysiology Aggressively manage the underlying ––provideprovide benefit in determining differential diagnosdiagnosisis –– provides no benefit in determining clinical disease management Similar pharmacologic management Galer Neuropathic Pain Assessment ––ProvidesProvides information about the type and degree of for neuropathic pains of diverse sensations felt. ––EvaluatesEvaluates 8 common qualities (sharp, dull, hot, colcold,d, etiologies sensitive (like raw skin or sunburn), itchy and deep versus surface pain) ––EachEach item is rated on a 0--100 10 scale

Galer BS, et al. Development and Preliminary Validation of a Pain Measure Specific to Neuropathic Pain: The Neuropathic Pain Scale. Neurology . 1997;48:3321997;48:332--338338 HT Benzon. The Neuropathic Pain Scales. Reg Anesth and Pain Med . 2005;30:4172005;30:417--421421

6 Drugs for Neuropathic Pain Antidepressants

Antidepressants Analgesic effect does not depend on antidepressant activity Anticonvulsants Effective dose often lower than Local Anesthetics antidepressant dose, onset of analgesia Opioids sooner Others Block reuptake of norepinephrine and serotonin in spinal cord: affect modulation, enhance descending inhibitory pathways

Antidepressants Tricyclic Antidepressants

Tricyclics Amitriptyline, imipramine, NonNon--tricyclictricyclic dual reuptake inhibitors clomipramine, nortriptyline, (SNRIs) desipramine, maprotiline venlafaxine and duloxetine Most studied, particularly for diabetic SSRIs neuropathy pain All are effective antidepressants Generally least tolerated in elderly SSRIs not conclusively proven effective against NP Risk of conduction abnormalities: get baseline EKG

7 Tricyclics Side Effects

Advantages Sedation (often helpful) can get some relief with most chronic Orthostatic hypotension pain syndromes Anticholinergic effects no end organ damage Dry mouth Blurred vision Disadvantages Urinary retention side effects persistent and troublesome Constipation many pain syndromes don’t respond well Weight gain Cardiac arrhythmia (usually atrial therapeutic ceiling tachycardias)

Serotonin and Norepinephrine Tricyclics Reuptake Inhibitors (SNRIs) Drug Trade Starting Sedation Anticholinergic Orthostatic duloxetine ((CymbaltaCymbalta ®®)) Name Dose Hypotension (Range) first drug released for both depression and NP Amitriptyline Elavil 2525--7575 +++ +++ ++++ 60 mg/d nausea : start with 30 mg/d Desipramine Norpramin 5050--100100 ++ ++ ++++ effect within a week? venlafaxine ((EffexorEffexor ®®)) Doxepin Sinequan 1010--5050 +++ +++ ++++ fewer side effects than TCAs 75 mg/d, increase by 75 mg each week; max 225 mg/d of Imipramine Tofranil 2525--5050 ++++ ++++ ++++ extended release; 375 mg/d standard drug effect in 22--44 weeks Nortriptyline Pamelor 1010--5050 ++ ++ ++++ desvenlafaxine ((PristiqPristiq ®®)) milnacipran ((SavellaSavella ®®))

8 Traditional SSRIs Anticonvulsants

Evidence for modest analgesic effect Carbamazepine (Tegretol) with paroxetine and citalopram Phenytoin (Dilantin) Others by relieving depression, may reduce pain Valproic acid (Depakote) Most prescribed antidepressants Clonazepam (Klonopin) Drugs of choice for GAD SSRIs inhibit CYP 2D6

22ndnd Generation Gabapentin Anticonvulsants αα δδ Gabapentin ((NeurontinNeurontin)) Blocks 22 subunit of voltagevoltage--dependentdependent calcium channel Pregabalin ((LyricaLyrica)) Reduce influx of Ca 2+2+ , less glutamate released from nerve endings Lamotrigine ((LamictalLamictal)) Not metabolized, few drug interactions Topiramate ((TopamaxTopamax)) Sedation common; ataxia, peripheral Tiagabine ((GabitrilGabitril)) edema, dizziness, diplopia, nausea Start 100100--300300 mg tid Levetiracetam ((KeppraKeppra)) At least 1800 mg/d usually needed Oxcarbazepine ((TrileptalTrileptal)) 36003600--48004800 mg/d good trial Zonisamide ((ZonegranZonegran))

9 Gabapentin Pregabalin (Lyrica ®®))

αα δδ Gabapentin absorbed by an LL--aminoamino Also an 22 ligand with analgesic, acid transporter in the proximal small anxiolytic and anticonvulsant activity bowel 6X stronger binding than gabapentin Capacity limited, becomes saturated at Linear pharmacokinetics, rapid onset, high doses and few drug interactions 150150--600mg/day600mg/day--lowlow subject variability Improved pain and sleep A controlled substance

Anticonvulsants: Side Effects

Carbamazepine*: sedation, dizziness, nausea, unsteadiness, 2% leukopenia, thrombocytopenia Phenytoin*: sedation, mental clouding, unsteadiness Valproic acid*: sedation, nausea, tremor Clonazepam: drowsiness, ataxia Gabapentin: sedation, dizziness, nausea Lamotrigine: rash, StevensStevens--JohnsonJohnson syndrome

*teratogenic

10 Local Anesthetics Topical Lidocaine

Block sodium channels ––thatthat blocks Maximum of 3 patches daily for a the action potential maximum of 12 hours Suppress abnormal electrical activity No titration needed or hypersensitivity in neural structures Two weeks provides an adequate involved in causing the pain therapeutic trial Can treat with IV lidocaine Can cut the patch to fit the painful area

Opioid Analgesics Opioid Analgesics

Degree of response may be less than Morphine: start with 1010--3030 mg every seen with nociceptive pain 4 hours; may increase by 2020--30%30% per Controlled release opioids and day oxycodone have been studied If pain is persistent, switch to a longlong-- Sedation, nausea, constipation, itching acting or controlled release opioid are common side effects once the daily dose requirements are known

Eisenberg E, et al. Efficacy and Safety of Opioid Agonists in the Treatment of Neuropathic Pain of Nonmalignant Origin JAMA 2005; 293: 30433043--305305 44--66 weeks an adequate trial period

11 Opioid Analgesics Tramadol (Ultram)

Advantages: efficacy, no ceiling Some weak morphinemorphine--likelike activity effect, no end organ damage Weak inhibitor of norepinephrine and Disadvantages: significant side effects serotonin reuptake Start with 50 once or twice daily Uncertain as to risks vs benefits of longlong--termterm therapy Increase by 5050--100100 mg per day to maximum of 400 mg/day Many adverse effects reported: dizziness/vertigo, nausea, constipation, headache, sleepiness

Other drugs that may benefit Management of persons with persistent pain Neuropathic Pain

Capsaicin Should be multidimensional Drug therapy Ketamine Psychological intervention Baclofen Treat underlying cause; maintain blood sugar in diabetics, Clonidine hyperglycemia can result in peripheral Tizanidine nerve injury Vaccinate against herpes zoster

Oxman MN, et al. A Vaccine to Prevent Herpes Zoster and Postherpetic Neuralgia in Older Adults. N Engl J Med 2005; 352: 22712271--22842284

12 Pharmacologic FirstFirst--LineLine Drugs for NP Management

FirstFirst--lineline treatments have been Not in order of preference identified Antidepressants Tricyclic antidepressants Current practice: “Trial and Error” Venlafaxine and duloxetine There may be advantages to Alpha 22--deltadelta ligands (calcium channel subunits) combining two firstfirst--lineline drugs Gabapentin and pregabalin Topical analgesics: 5% lidocaine patch Systemic analgesics Opioids and tramadol Gilron I, et al. Morphine, Gabapentin, or Their Combination for Neuropathic Pain. N Eng J Med . 2005;352:13242005;352:1324--13341334 Dworkin RH, et al. Advances in Neuropathic Pain: Diagnosis, Mechanisms, and Treatment Recommendations. Arch Neurol 2003; 60: 15241524--15341534

Example Treatment Algorithm Pharmacological Targets 5HT NE α Na Ca GABA Glu NMDA Painful Neuropathy Antidepressants TCA Amitriptyline 3° amine Nortriptyline 2° amine FirstFirst--lineline agents SSNRI Venlafaxine + Duloxetine Lidocaine 5% SSRI Gabapentin Opioids Tramadol TCAs Patch Anticonvulsants Traditional Carbamazepine Phenytoin Oxcarbazepine ? Continue yes Newer Agents Gabapentin ? ? Treatment Response Lamotrigine Topiramate ? +/- ? partial or no response Tiagabine Felbamate +/- Combine 2 or more 1 stst line agents (repeat as indicated) Zonisamide ? Levetiracetam ? Pregabalin ? ? Antiarrythimics Lidocaine, Mexiletine Continue yes Alpha Agonists Clonidine, Tizanidine Treatment Response Dexmedetomidine partial or no response NMDA Dextromethorphan, Methadone Ketamine, Memantine Consider 2 ndnd line medications GABA Agonist Baclofen

13 Analgesics Affect Different Parts of the Pain Pathway

Opioids Pain TCAs, SSNRIs, SSRIs? Newer AEs Anti-inflammatory agents ααα2-Agonists Descending modulation Ascending input Opioids TCAs, SSNRIs Newer AEs Dorsal Newer AEs Baclofen horn Anti-inflammatory agents NMDA antagonists ααα2-Agonists Dorsal root ganglion

Traditional AEs Local anesthetics

Peripheral Peripheral nociceptors nerve Anti-inflammatory agents Local anesthetics

Trauma

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