Review of Key Strategies for Managing Neuropathic Pain

Key Strategies for Managing Neuropathic Pain Copyright © 2005 Thomson Professional Postgraduate Services®. All rights reserved. IASP Definition of Pain “Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.” 2 Acute vs Chronic Pain Characteristic Acute Pain Chronic Pain Cause Generally known Often unknown Duration of pain Short, well-characterized Resolution of underlying cause, usually self-limited Persists after healing, 3 months Underlying cause and pain disorder; outcome is often pain control, not cure Treatment approach 3 Domains of Chronic Pain Quality of Life • Physical functioning • Ability to perform activities of daily living • Work • Recreation Psychological Morbidity • Depression • Anxiety, anger • Sleep disturbances • Loss of self-esteem Social Consequences • Marital/family relations • Intimacy/sexual activity • Social isolation Socioeconomic Consequences • Healthcare costs • Disability • Lost workdays 4 Nociceptive vs Neuropathic Pain Nociceptive Pain Caused by activity in neural pathways in response to potentially tissue-damaging stimuli Mixed Type Caused by a combination of both primary injury and secondary effects Neuropathic Pain Initiated or caused by primary lesion or dysfunction in the nervous system CRPS* Postoperative pain Mechanical low back pain Arthritis Sickle cell crisis Postherpetic neuralgia Neuropathic low back pain Trigeminal neuralgia Sports/exercise injuries 5 *Complex regional pain syndrome Distal polyneuropathy (eg, diabetic, HIV) Central poststroke pain Possible Descriptions of Neuropathic Pain • Sensations – – – – – – – – – – 6 • Signs/Symptoms – allodynia: pain from a stimulus that does not normally evoke pain • thermal • mechanical – hyperalgesia: exaggerated response to a normally painful stimulus numbness tingling burning paresthetic paroxysmal lancinating electriclike raw skin shooting deep, dull, bonelike ache Physiology of Pain Perception • Transduction Injury Brain • Transmission • Modulation • Perception • Interpretation Descending Pathway Dorsal Root Ganglion • Behavior Peripheral Nerve Ascending Pathways C-Fiber A-beta Fiber A-delta Fiber Dorsal Horn Spinal Cord 7 Adapted with permission from WebMD Scientific American® Medicine. Pathophysiology of Neuropathic Pain • • • • • • • Chemical excitation of nonnociceptors Recruitment of nerves outside of site of injury Excitotoxicity Sodium channels Ectopic discharge Deafferentation Central sensitization – maintained by peripheral input • Sympathetic involvement • Antidromic neurogenic inflammation 8 Multiple Pathophysiologies May Be Involved in Neuropathic Pain • More than one mechanism of action likely involved • Neuropathic pain may result from abnormal peripheral nerve function and neural processing of impulses due to abnormal neuronal receptor and mediator activity • Combination of medications may be needed to manage pain: topicals, anticonvulsants, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and opioids • In the future, ability to determine the relationship between the pathophysiology and symptoms/signs may help target therapy 9 Percentages of Herpes Zoster Patients With Persistent Pain 80 70 60 % of patients 50 40 30 20 10 0 0 1 month 1 year 19 29 39 49 Age (y) 59 69 70 10 Adapted from DeMorgas JM, Kierland RR. Arch Dermatol. 1957;75:193-196. What Are the Goals of Clinical Assessment? • • • • • • • • 11 Achieve diagnosis of pain Identify underlying causes of neuropathy Identify comorbid conditions Evaluate psychosocial factors Evaluate functional status (activity levels) Set goals Develop targeted treatment plan Determine when to refer to specialist or multidisciplinary team (pain clinic) Assessing the Patient With Pain • • • • • • • Onset and duration Location/distribution Quality Intensity Aggravating/relieving factors Associated features or secondary signs/symptoms Associated factors – mood/emotional distress – functional activities • Treatment response 12 Pain Treatment Continuum Least invasive Most invasive Continuum not related to efficacy Psychological/physical approaches Topical medications Systemic medications* Interventional techniques* 13 *Consider referral if previous treatments were unsuccessful. Nonpharmacologic Options • • • • Biofeedback Relaxation therapy Physical and occupational therapy Cognitive/behavioral strategies – meditation; guided imagery • Acupuncture • Transcutaneous electrical nerve stimulation 14 Pharmacologic Treatment Options • Classes of agents with efficacy demonstrated in multiple, randomized, controlled trials for neuropathic pain – topical analgesics (capsaicin, lidocaine patch 5%) – anticonvulsants (gabapentin, lamotrigine, pregabalin) – antidepressants (nortriptyline, desipramine) – opioids (oxycodone, tramadol) • Consider safety and tolerability when initiating treatment 15 FDA-Approved Treatments for Neuropathic Pain • Carbamazepine – trigeminal neuralgia • Duloxetine – peripheral diabetic neuropathy • Gabapentin – postherpetic neuralgia • Lidocaine Patch 5% – postherpetic neuralgia • Pregabalin* – peripheral diabetic neuropathy – postherpetic neuralgia 16 *Availability pending based upon controlled substance scheduling by the DEA. Pharmacologic Agents Affect Pain Differently BRAIN Descending Modulation Anticonvulsants Opioids Tricyclic/SNRI Antidepressants CNS Spinal Cord PNS Dorsal Horn Central Sensitization Anticonvulsants Opioids NMDA-Receptor Antagonists Tricyclic/SNRI Antidepressants Peripheral Sensitization Local Anesthetics Topical Analgesics Anticonvulsants Tricyclic Antidepressants Opioids 17 Topical vs Transdermal Drug Delivery Systems Topical (lidocaine patch 5%) Transdermal (fentanyl patch) Peripheral tissue activity Applied directly over painful site Insignificant serum levels Systemic side effects unlikely 18 Systemic activity Applied away from painful site Serum levels necessary Systemic side effects Lidocaine Patch 5% • Lidocaine 5% in pliable patch • Up to 3 patches applied once daily directly over painful site – 12 h on, 12 h off (FDA-approved label) – recently published data indicate 4 patches (18–24 h) safe • Efficacy demonstrated in 3 randomized controlled trials on postherpetic neuralgia • Drug interactions and systemic side effects unlikely – most common side effect: application-site sensitivity • Clinically insignificant serum lidocaine levels • Mechanical barrier decreases allodynia 19 Anticonvulsant Drugs for Neuropathic Pain Disorders • Postherpetic neuralgia – gabapentin* – pregabalin * • HIV-associated neuropathy – lamotrigine • Trigeminal neuralgia – carbamazepine* – lamotrigine – oxcarbazepine • Diabetic neuropathy – – – – – carbamazepine phenytoin gabapentin lamotrigine pregabalin * • Central poststroke pain – lamotrigine 20 *Approved by FDA for this use. HIV = human immunodeficiency virus. Gabapentin in Neuropathic Pain Disorders • • • • FDA approved for postherpetic neuralgia Anticonvulsant: uncertain mechanism Limited intestinal absorption Usually well tolerated; serious adverse effects rare – dizziness and sedation can occur • No significant drug interactions • Peak time: 2 to 3 h; elimination half-life: 5 to 7 h • Usual dosage range for neuropathic pain up to 3,600 mg/d (tid–qid)* 21 *Not approved by FDA for this use. Antidepressants in Neuropathic Pain Disorders* • Multiple mechanisms of action • Randomized controlled trials and meta-analyses demonstrate benefit of tricyclic antidepressants (especially amitriptyline, nortriptyline, desipramine) for postherpetic neuralgia and diabetic neuropathy • Onset of analgesia variable – analgesic effects independent of antidepressant activity • Improvements in insomnia, anxiety, depression • Desipramine and nortriptyline have fewer adverse effects 22 *Not approved by FDA for this use. Tricyclic Antidepressants: Adverse Effects • Commonly reported AEs (generally anticholinergic): – – – – – – – – – blurred vision cognitive changes constipation dry mouth orthostatic hypotension sedation sexual dysfunction tachycardia urinary retention Fewest AEs • Desipramine • Nortriptyline • Imipramine • Doxepin • Amitriptyline Most AEs 23 AEs = adverse effects. Principles of Opioid Therapy for Neuropathic Pain • Opioids should be titrated for therapeutic efficacy versus AEs • Fixed-dose regimens generally preferred over prn regimens • Document treatment plan and outcomes • Consider use of opioid written care agreement • Opioids can be effective in neuropathic pain • Most opioid AEs controlled with appropriate specific management (eg, prophylactic bowel regimen, use of stimulants) • Understand distinction between addiction, tolerance, physical dependence, and pseudoaddiction 24 Distinguishing Dependence, Tolerance, and Addiction • Physical dependence: withdrawal syndrome arises if drug discontinued, dose substantially reduced, or antagonist administered • Tolerance: greater amount of drug needed to maintain therapeutic effect, or loss of effect over time • Pseudoaddiction: behavior suggestive of addiction; caused by undertreatment of pain • Addiction (psychological dependence): psychiatric disorder characterized by continued compulsive use of substance despite harm 25 Interventional Treatments for Neuropathic Pain • Neural blockade – sympathetic blocks for CRPS-I and II (reflex sympathetic dystrophy and causalgia) • Neurolytic techniques – alcohol or phenol neurolysis – pulse radio frequency • Stimulatory techniques – spinal cord stimulation – peripheral nerve stimulation • Medication pumps 26 CRPS = complex regional pain syndrome. Summary of Advances in Treatments for Neuropathic Pain* • Botulinum toxin: low back pain • Lidocaine patch 5%: low back pain, osteoarthritis, diabetic and HIV-related neuropathy, with gabapentin • CR oxycodone: diabetic neuropathy • Gabapentin: HIV-related neuropathy, diabetic peripheral neuropathy, others • Levetiracetam: neuropathic pain and migraine • Oxcarbazepine: neuropathic pain; diabetic neuropathy • Bupropion: neuropathic pain • Transdermal fentanyl: low back pain 27 *Applications not approved by FDA. Summary • Chronic neuropathic pain is a disease, not a symptom • “Rational” polypharmacy is often necessary – combining peripheral and central nervous system agents enhances pain relief • Treatment goals include: – balancing efficacy, safety, and tolerability – reducing baseline pain and pain exacerbations – improving function and QOL • New agents and new uses for existing agents offer additional treatment options 28