Nocioceptive Pain Pathophysiology of Pain Larry Levine, MD Alaska Spine Institute Ex: Acute Postoperative Pain Noxious peripheral Stimuli Heat/Cold Mechanical Force Chemical Irritants Nociceptive Pain Inflammatory Pain Noxious peripheral Stimuli Nociceptor sensory Neuron Pain Autonomic response, Withdrawal Reflex Spinal Cord and Brain A High Pain Threshold Response Ex: active RA, acute OA flare Inflammation Macrophage Mast Cell Neutrophil Granulocyte Tissue Damage Inflammatory Pain Neuropathic Pain Spontaneous Pain Pain Hypersensitivity Reduced Threshold allodynia Increased Response Hyperalgesia Ex: Diabetic Peripheral Neuropathic Pain Post Herpetic Neuralgia 1
Neuropathic Pain Peripheral Nerve Damage Spontaneous Pain / Pain Hypersensitivity Reduced Threshold: allodynia Increased response: hyperalgesia Pain Associated with Central Augmentation Fibromyalgia Pain Associated with Central Augmentation Normal Peripheral Tissue and Nerves*** Abnormal Central Processing in Spinal Cord and Brain Spontaneous Pain/ Pain Hypersensitivity Allodynia / Hyperalgesia Action Sites: Peripheral Nocioceptors Transduction Acetaminophen anticonvulsants ASA Capsaicin Local Anesthetics Nitrates NSAIDS Action Site: Transmission, Peripheral Nerve Action:Transmission, DRG, Dorsal Horn Local Anesthetics Opiods alpha 2 agonists, local anesthetics 2
Action: Modulation, Brain Stem, Cord (Descending Modulation) SNRI s, SSRI s, Local Anesthetics Action: Perception, Brain alpha 2 adrenergic agonists opiods SNRI s SSRI s TCA s Pain Nociception An unpleasant sensory and emotional experience which we primarily associate with tissue damage or describe in terms of such damage, or both The detection of tissue damage by specialized transducers connected to A-delta and C-fibers Classification of Pain Nociception Classification of Pain: Neuropathic Pain Proportionate to the stimulation of the nociceptor When acute Physiologic pain Serves a protective function Normal pain Pathologic when chronic Sustained by aberrant processes in PNS or CNS Disproportionate to the stimulation of nociceptor Serves no protective function Pathologic pain 3
Classification of Pain: Mixed Pain Classification of Pain: Idiopathic Pain Nociceptive components Neuropathic components Examples Failed low-back-surgery syndrome Complex regional pain syndrome No underlying lesion found yet, despite investigation Pain disproportionate to the degree of clinically discernible tissue injury Peripheral and Central Pathways for Pain Ascending Tracts Descending Tracts Normal Central Pain Mechanisms Thalamus Cortex Midbrain Pons Medulla Spinal Cord Pain-Inhibitory and Pain-Facilitatory Mechanisms Within the Dorsal Horn Neuronal circuitry within the dorsal horn. Primary afferent neuron axons synapse onto spinothalamic neurons and onto inhibitory and excitatory neurons. 0 A- BETA A- DELTA + STT + NEURON + + TO BRAIN C Mechanisms of Pathologic Pain 4
Mechanisms of Pathophysiologic Pain: Peripheral Processes Mechanisms of Pathophysiologic Pain: Central Sensitization Processes Injured or diseased nerve(s) Growth of axonal sprouts Formation of ectopic foci Repeated impulse activity in C nociceptive neurons produces sensitization of STT neurons over time Sensitization of STT neurons leads to Increased spontaneous impulse activity Enhanced responses to impulses in nociceptive and non-nociceptive primary afferents Causes hyperalgesia, allodynia, and spontaneous pain Mechanism of Central Sensitization Associated With Tonic C Nociceptor Input 0 A- BETA A- DELTA + STT + + + NEURON + + + + TO BRAIN C Tonic activity in C nociceptors Enhanced postsynaptic effects by NMDA-receptor sensitization Intracellular Mechanisms of Sensitization Reproduced with permission from Mao J, et al. Pain. 1995;61:361. Loss of Inhibitory Interneuron Function 0 A- BETA A- DELTA + STT + + + NEURON + + + + TO BRAIN C Tonic activity in C nociceptors Enhanced postsynaptic effects by NMDA-receptor sensitization Brain-to-Spinal-Cord Modulation of Pain 5
Pain Modulation Mechanisms Pathophysiology of Pain: Conclusion Brain centers/pathways that descend to the spinal cord and modulate pain Tail-flick test Off-cells inhibit transmission of pain-related information to the brain On-cells facilitate transmission of painrelated signals to the brain Neuronal plasticity Nociceptor, spinal cord, brain Pain-facilitatory and pathophysiologic mechanisms Wind-up phenomenon Central sensitization Modulating mechanisms Ascending Descending Nociceptive Pain Sensitization and activation of healthy nociceptor endings and recruitment of silent nociceptors Soup of inflammatory algogenic agents, such as protons, prostaglandins, bradykinin, serotonin, adenosine, histamine, cytokines Neuropathic Pain Mechanisms of Neuropathic Pain Pathophysiology of Neuropathic Pain Noninflammatory states Inflammatory states Ectopic activity in the peripheral pathways, including axons and DRG CNS mechanisms 6
Neuropathic Pain: Central Mechanisms Peripheral neuropathic events can be complicated by temporary or long-term CNS changes, such as central sensitization and then reorganization of the pain pathways at the dorsal horn level Neuropathic Pain and SMP Some neuropathic pains are sustained, at least in part, by sympathetic efferent activity SMP Expression of alpha-adrenergic receptors on injured C-fibers may be a relevant mechanism of SMP, but others are possible Clinical findings consistent with CRPS signal an increased likelihood of SMP PNS peripheral nervous system CNS central nervous system Nociceptive Pain Healthy nociceptors Peripheral sensitization Normal Central transmission sensitization Pappagallo M. 2001. Physiologic state Neuropathic Pain Abnormal nociceptors PNS Central reorganization Pathologic state CNS Neuropathic Pain Diverse syndromes with uncertain classification Mononeuropathies and polyneuropathies CRPS Deafferentation syndromes, including central pain Fibromyalgia as a Clinical Model for Pharmacology of Pain Pathogenesis Higher levels Nitric Oxide Lower Phosphorylation Potential Lower Oxidative Capacity Thus lower levels ATP Increased Levels Substance P, IL -1 > DNA Fragmentation Perfusion Deficits Appears to represent difference in muscle metabolism 7
Neural Structure Changes NMDA N-methyl-D-Aspartate receptor changes Glutamate binds to NR2 Subunits of NMDA in the DRG and skin Upregulation of NR@ subunits in those with fibromyalgia(159 vs 100 p=0.016) Electron microscopy shows Schwann Cell fiber ballooning, axon peripheralization, smaller axon size, simplified folding structures Changes in opiod receptors: up regulation of delta and kappa receptors. Neuroendocrine changes decreased response to ACTH, epi under stresses CSF Changes in Biochemicals Lower serum serotonin levels Lower norepinepherine levels Lower dopamine levels Higher substance P levels Higher Nerve Growth Factor levels Possible candidate genes related to FMS HLA DR4 antigen D2 and D4 Dopamine receptors on chrom 11 Substance P receptor (NK1) Symptoms with FMS Symptoms with FMS Neuro < concentration Dizziness Headache Psychiatric Anxiety Depression Fear, anger, guilt GI Abd Pain Bloating Constipation Diarrhea GU Pelvic Pain Urinary Burning, Frequency 8
Symptoms with FMS FMS Constitutional Symptoms Fatigue/Generalized Weakness Night Sweats Weight Fluctuations Functional MRI coorelates Changes noted but what does it mean still up for discussion: clear alteration in processing of pain. Medications: Antiepileptic TCA SSRI SNRI Analgesic Muscle Relaxants 1st Line Cyclobenzaprine Duloxetine(Cymbalta) Milnacipran (Savella) Pregabalin (Lyrica) TCA s amitriptyline 2nd Line SSRI (fluoxetine Prozac, citalopram Celexa) Tramadol Venlafaxine (Effexor) Not Recommeded Benzos Calcitonin Guaifenesin Melatonin NSAID s Opiods Steroids Thyroid Hormone 9
Nonpharmacological Treatments 1st Line Aerobic Exercise Cognitive Behavioral Therapy Patient Education 2nd Line Acupuncture Biofeedback Hypnotherapy Strength Training Nonpharmacological 3 rd Line Chiropractic Electrotherapy Massage Ultrasound Diagnosing and Treating Fibromyalgia: Present and Future Considerations. Bernstein, Marcus, Pain Medicine News, December 2009 Opiod Considerations Strong Relationship between THCA positivity and other illicit substances. Pain Practice 13% THCA > 3.7 ration of other illicit drugs in those THCA positive including cocaine 4.6 % total, methamphetamine 1.07% Marijuana Correlates with Use of Other Illicit Drugs in a Pain Patient Population, Pesce et al, Pain Physician 2010 Opiod Considerations Neuropathic Pain: Clinical Characteristics Benzos Predict Use of Opioids A Follow-UP Study of 17074 Men and Women, Skurtveit et al, Pain Medicine 2010;11 Earlier use of benzodiazepines may predict repeated use of opiods. Odds ratio for opiod use at moderate-high prescription frequency is 7.7 (95% confidence interval) as compared with non users. Use of benzos is stronger predictor of opiod use then self reported chronic pain. Burning, shooting, electrical-quality pain May be aching, throbbing, sharp Neuropathic sensations: dysesthesias, paresthesias 10
Neuropathic Sensations Paresthesias: abnormal; spontaneous, intermittent, painless Dysesthesias: abnormal; spontaneous or touch-evoked, unpleasant Neuropathic Pain: Evoked Dysesthesias Allodynia: pain elicited by a nonnoxious stimulus (clothing, air movement, touch) Mechanical (induced by light pressure) Thermal (induced by a nonpainful cold or warm stimulus) Hyperalgesia: exaggerated pain response to a mildly noxious (mechanical or thermal) stimulus Hyperpathia: delayed and explosive pain response to a noxious stimulus Primary Hyperalgesia Secondary Hyperalgesia Present in the primary zone, at the location of injury Characterized by pinprick hyperalgesia + warm and heat hyperalgesia + static mechanical allodynia (tenderness) Indicative of PNS sensitization Present in the zone surrounding an injury Characterized by dynamic mechanical allodynia + cold hyperalgesia Indicative of CNS sensitization Neuropathic Pain: Management Neuropathic Pain: Pharmacologic Therapies Pharmacotherapy Nonopioid Opioid Adjuvant analgesics Interventional Neural blockade (eg, sympathetic nerve blocks) Neurostimulatory techniques (eg, spinal cord stimulation) Intraspinal infusion Gabapentin, carbamazepine, lamotrigine, and newer AEDs Antidepressants Opioid analgesics Lidocaine (transdermal, intravenous [IV]), mexiletine Alpha-2 adrenergic agonists 11
Disk Herniation With Sciatica 90% of ruptured disks at L4-L5 and L5- S1 90% of patients with back pain and sciatica will recover without surgery At least 50% within 6 wk Low Back Pain and Sciatica: Nociceptive/ Inflammatory Pain Mechanisms Activation and sensitization of the nerve root nervi nervorum from root compression/traction Sensitization of the nociceptors of the annulus fibrosus, periosteal spinal structures, and ligaments, due to acute inflammation, eg, status post trauma Hyperalgesia (deep spinal and dermatomal) due to central sensitization Radicular and Discogenic Neuropathic Pain Mechanisms Ectopic activity of the nerve root nervi nervorum Sensitization and ectopic activity of the nociceptors innervating spinal periosteal structures, ie, annuli and ligaments Possible role of abnormal nociceptors overgrown within the intradiscal space, postsurgical epidural scars, degenerated facet joints CNS sensitization and reorganization Failed-Back-Surgery Syndrome Reoperations 60% due to post spinal surgery complications 40% due to uncorrected or new structural abnormalities of the spine Failed-Back-Surgery Syndrome Management of Back Pain Postsurgical causes of back pain Recurrent or retained disk fragment Postoperative instability Dural adhesions Root injury Arachnoiditis Pseudomeningocele Failure to relieve the original pathologic condition Postoperative wound and disk infection Pharmacologic agents Opioid analgesics Anti-inflammatories Adjuvants and nonopioid analgesics Nonpharmacologic therapies Rehabilitative Interventional 12
Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Acetaminophen Inhibition of cyclooxygenase activity COX-1 and COX-2 drugs Toxicity: Gastrointestinal, renal, platelet aggregation Multiple drugs Ceiling dose effect Peripheral and central analgesic action Minimal anti-inflammatory action Central analgesia No GI or platelet-aggregation toxicity Serious dose-dependent hepatotoxicity Ceiling dose effect Nonopioid Adjuvant Analgesics Antidepressants TCAs (nortriptyline, amitriptyline, desipramine) SSRIs (paroxetine, sertraline, fluoxetine) Venlafaxine Alpha 2-adrenergic agonists TCA = tricyclic antidepressant; SSRI = selective serotonin reuptake inhibitor Tizanidine, clonidine Nonopioid Adjuvant Analgesics Gabapentin Carbamazepine Clonazepam Valproate Antiepileptics and Antiarrhythmics Lamotrigine Tiagabine Topiramate Oxcarbazepine Zonisamide Mexiletine Pharmacotherapy for Pain Pharmacotherapy of Pain Categories of analgesic drugs Opioid analgesics Nonopioid analgesics Adjuvant analgesics Drugs for headache 13
Evolving Role of Opioid Therapy Positioning Opioid Therapy Historically, opioids have been emphasized in medical illness and de-emphasized in nonmalignant pain Consider as first-line for patients with moderate-tosevere pain related to cancer, AIDS, or another life-threatening illness Consider for all patients with moderate-to-severe noncancer pain, but weigh the influences What is conventional practice? Are opioids likely to work well? Are there reasonable alternatives? Are drug-related behaviors likely to be responsible, or problematic so as to require intensive monitoring? Opioid Therapy: Prescribing Principles Opioid Therapy: Drug Selection Prescribing principles Drug selection Dosing to optimize effects Treating side effects Managing the poorly responsive patient Immediate-release preparations Used mainly For acute pain For dose finding during initial treatment of chronic pain For rescue dosing Can be used for long-term management in select patients Opioid Therapy: Drug Selection Opioid Therapy: Drug Selection Immediate-release preparations Combination products Acetaminophen, aspirin, or ibuprofen combined with codeine, hydrocodone, dihydrocodeine Single-entity drugs, eg, morphine, oxycodone, oxymorphone, others Tramadol Extended-release preparations Preferred because of improved treatment adherence and the likelihood of reduced risk in those with addictive disease Morphine, oxycodone, oxymorphone, fentanyl, hydromorphone, codeine, tramadol, buprenorphine 14
Opioid Therapy: Drug Selection Opioid Selection: Poor Choices for Chronic Pain Role of methadone Another useful long-acting drug Unique pharmacology when commercially available as the racemic mixture Potency greater than expected based on single-dose studies When used for pain: multiple daily doses, steady-state in 1 to several weeks Close monitoring needed until steady-state approached to reduce risk of side effects Meperidine Poor absorption and toxic metabolite Propoxyphene Poor efficacy and toxic metabolite Mixed agonist-antagonists (pentazocine, butorphanol, nalbuphine, dezocine) Compete with agonists withdrawal Analgesic ceiling effect Opioid Therapy: Routes of Administration Opioid Therapy: Guidelines Oral and transdermal preferred Oral transmucosal available for fentanyl and used for breakthrough pain Rectal route limited use Parenteral SQ and IV preferred and feasible for long-term therapy Intraspinal intrathecal generally preferred for long-term use Consider use of a long-acting drug and a rescue drug usually 5% 15% of the total daily dose Baseline dose increases: 25% 100% or equal to rescue dose use Increase rescue dose as baseline dose increases Treat side effects Opioid Therapy: Side Effects Nonopioid Analgesics Common Constipation Somnolence, mental clouding Less common Nausea Sweating Myoclonus Amenorrhea Itch Sexual dysfunction Urinary retention Headache Acetaminophen (paracetamol) Dipyrone Nonsteroidal anti-inflammatory drugs 15
Nonopioid Analgesics NSAIDs Acetaminophen (paracetamol) Minimal anti-inflammatory effects Fewer adverse effects than other nonopioid analgesics Adverse effects Renal toxicity Risk for hepatotoxicity at high doses Increased risk with liver disease or chronic alcoholism No effect on platelet function Mechanism Inhibit both peripheral and central cyclooxygenase, reducing prostaglandin formation 3 isoforms of COX COX-1: Constitutive, physiologic COX-2: Inducible, inflammatory COX-3: Central, blocked by acetaminophen NSAIDs NSAIDs Properties Nonspecific analgesics, but greater effectiveness likely in inflammatory pains Dose-dependent effects, with ceiling dose Marked individual variation in response to different drugs Drug-to-drug variation in toxicities partly determined by COX-1/COX-2 selectivity Properties Adverse effects: GI toxicity, renal toxicity, cardiovascular toxicity, bleeding diathesis, prothrombotic effects GI toxicity reduced by PPIs, misoprostol, and possibly high-dose histamine-2 blockers COX-2 selective inhibitors have better GI safety profile Use with caution in patients with renal insufficiency Use with caution in patients with atherosclerotic disease, congestive heart failure, or hypertension NSAIDs NSAIDs Chemical Class Nonacidic Acidic Salicylates Generic Name nabumetone aspirin, diflunisal, choline magnesium trisalicylate, salsalate Chemical Class Acidic Acetic acids Oxicams Generic Name indomethacin, tolmetin, sulindac, diclofenac, ketorolac meloxicam, piroxicam Proprionic acids ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin Fenamates Selective COX-2 inhibitors mefenamic acid, meclofenamic acid celecoxib 16
NSAIDs Adjuvant Analgesics Drug selection should be influenced by drug-selective toxicities, prior experience, convenience, cost Relative cost-benefit of COX-2 selective drugs and nonselective drugs combined with gastroprotective therapy is not known Defined as drugs with other indications that may be analgesic in specific circumstances Numerous drugs in diverse classes Sequential trials are often needed Adjuvant Analgesics Multipurpose Adjuvant Analgesics Multipurpose analgesics Drugs used for neuropathic pain Drugs used for musculoskeletal pain Drugs used for cancer pain Drugs used for headache Class Antidepressants Alpha-2 adrenergic agonists Corticosteroids Examples amitriptyline, desipramine, nortriptyline, duloxetine, venlafaxine, paroxetine, others tizanidine, clonidine prednisone, dexamethasone Multipurpose Adjuvant Analgesics Multipurpose Adjuvant Analgesics Antidepressants Best evidence: 3 0 amine TCAs (e.g., amitriptyline) 2 0 amine TCAs (desipramine, nortriptyline) better tolerated and also analgesic Evidence for the SSNRIs, e.g., duloxetine, and little evidence in favor of SSRIs/atypical antidepressants (e.g., paroxetine, bupropion, others); these are better tolerated yet Alpha-2 adrenergic agonists Clonidine and tizanidine used for chronic pain of any type Tizanidine usually better tolerated Tizanidine starting dose 1 2 mg/d; usual maximum dose up to 40 mg/d 17
Adjuvant Analgesics for Neuropathic Pain Adjuvant Analgesics for Neuropathic Pain Class Anticonvulsants lamotrigine carbamazepine, Examples gabapentin, pregabalin, valproate, phenytoin, Class NMDA receptor Antagonists Examples dextromethorphan, ketamine, clonazepam, topiramate, levetiracetam tiagabine, amantadine Miscellaneous baclofen, calcitonin oxcarbazepine, zonisamide Topical lidocaine, Local anesthetics mexiletine, tocainide lidocaine/prilocaine, capsaicin, NSAIDs Adjuvant Analgesics for Neuropathic Pain Anticonvulsants Gabapentin or pregabalin commonly used Favorable safety profile and positive RCTs in PHN/diabetic neuropathy Analgesic effects supported for phenytoin, carbamazepine, valproate, clonazepam, and lamotrigine Limited experience with other drugs Adjuvant Analgesics for Neuropathic Pain Local anesthetics Oral therapy with mexiletine, tocainide, flecainide IV/SQ lidocaine also useful Useful for any type of neuropathic pain Adjuvant Analgesics for Neuropathic Pain Adjuvant Analgesics for Neuropathic Pain Miscellaneous drugs Calcitonin RCTs in CRPS and phantom pain Limited experience Baclofen RCT in trigeminal neuralgia 30 200 mg/d or higher NMDA-receptor antagonists N-methyl-D-aspartate receptor involved in neuropathic pain Commercially-available drugs are analgesic: ketamine, dextromethorpan, amantadine 18
Topical Adjuvant Analgesics Adjuvant Analgesics for Musculoskeletal Pain Used for neuropathic pain Local anesthetics Lidocaine patch Cream, eg, lidocaine 5%, EMLA Capsaicin Used for musculoskeletal pains NSAIDs Muscle relaxants Refers to numerous drugs, eg, cyclobenzaprine, carisoprodol, orphenadrine, methocarbamol, chlorzoxazone, metaxalone Centrally-acting analgesics Do not relax skeletal muscle Adjuvant Analgesics for Cancer Pain Adjuvant Analgesics for Chronic Headache For bone pain Bisphosphonates (eg, pamidronate, clodronate), calcitonin, radiopharmaceuticals (eg, Sr 89, Sm 153 ) For bowel obstruction pain Anticholinergics, octreotide Beta blockers Anticonvulsants Calcium channel blockers Alpha-2 adrenergic agonists Antidepressants Vasoactive drugs ACE inhibitors Pathophysiology Nociceptive pain Neuropathic pain Idiopathic pain Psychogenic pain Commensurate with identifiable tissue damage May be abnormal, unfamiliar pain, probably caused by dysfunction in PNS or CNS Pain, not attributable to identifiable organic or psychologic processes Sustained by psychologic factors Nociceptive Pain Presumably related to ongoing activation of primary afferent neurons in response to noxious stimuli Pain is consistent with the degree of tissue injury Subtypes Somatic: well localized, described as sharp, aching, throbbing Visceral: more diffuse, described as gnawing or cramping 19
Neuropathic Pain Pain believed to be sustained by aberrant somatosensory processing in the peripheral or central nervous system Subtypes Central generator Deafferentation pain (central pain, phantom pain) Sympathetically-maintained pain (CRPS) Peripheral generator Originate in the nerve root, plexus, or nerve Polyneuropathies, mononeuropathies Novel Drug Therapies for Pain Central Nociception: Emerging Analgesic Targets Excitatory amino acid and NK receptors N-type Ca ++ receptors N-acetylcholine receptors Adenosine (A 1 ) receptors Cannabinoid (CB1) receptors n-6 HUFA highly unsaturated fatty acids, and trans fatty acid levels higher in CRPS Peripheral Nociception: Emerging Analgesic Targets Sensory neuron specific Na + channels (eg, PN3, NAN) Opioid receptors Vanilloid receptors Serotonin receptors Botox Injections (Joints) unknown mechanism research appears solid Peripheral Nociception: Emerging Analgesic Targets Nonopioid Analgesics and Adjuvants for Inflammatory Neuropathic Pain States Alpha-adrenergic receptors Proton-sensitive channels (ph-sensitive) Nerve growth-factor receptors (TrKA, p75) N- or T-type Ca ++ channels Purine receptors Anticytokines (eg, anti TNF-alpha antibodies, thalidomide, IV bisphosphonates) TrKA = tyrosine kinase 20
Adjuvant Analgesics With Opioid Interactions NMDA antagonists (eg, dextromethorphan, ketamine, amantadine) Cholecystokinin-B antagonists (eg, proglumide) Ultra-low doses of opioid antagonists 21