*With the exception of programs from the ACCEL series, each of which qualifies for up to 4 Category 1 CME credits.
Volume 04, Issue 13
July 7, 2013
Nociception; Pain; Components of pain: Neuropathic pain; Complex regional pain syndrome: Mechanisms of chronic neuropathy: How migraine mechanism differs Steven Graff-Radford, DDS
From Current Concepts And Challenges In The Management Of Pain, Sponsored By Cedars-sinai Pain Center
The following is an abstracted summary, not a verbatim transcript, of the lectures/discussions on this audio program.
Neurology Program Info Accreditation InfoCultural & Linguistic Competency Resources
Mechanisms of Pain and Assessing Pain-Management Targets
From Current Concepts and Challenges in the Management of Pain, sponsored by Cedars-Sinai Pain Center
Steven Graff-Radford, DDS, Adjunct Professor, University of California, Los Angeles, School of Dentistry; Clinical Professor, University of Southern California School of Dentistry, Los Angeles; and Director, Program for Headache and Orofacial Pain, Cedars-Sinai Pain Center, Cedars-Sinai Medical Center, Los Angeles
The goal of this program is to improve the management of pain through specific knowledge of pain mechanisms and treatment targets. After hearing and assimilating the information in this program, the clinician will be better able to:
1. Describe nociception and its role in pain processing.
2. Differentiate acute and chronic pain by mechanism, presentation, and management.
3. Identify the clinical signature of neuropathic pain and at-risk populations.
4. Summarize neurochemical abnormalities associated with chronic neuropathies.
5. Recognize potential treatment targets among the mechanisms neuropathic pain
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Graff-Radford is on the Speakers’ Bureau and is a consultant for Zogenix; he receives research support from Allergan, MAP Pharmaceuticals, and Pfizer. The planning committee reported nothing to disclose. In his lecture, Dr. Graff-Radford presents information that is related to the off-label or investigational use of a therapy, product, or device.
Nociception: defined by International Association for the Study of Pain (IASP) as potentially tissue-damaging thermal, mechanical, or chemical energy that impinges upon specialized nerve endings, namely A-delta and C fibers; stimulation of any peripheral area with these energies produces messages to various parts of neural system
Sensory cortex: anatomic distribution of homunculus in sensory cortex allows brain to identify where in body message originates and interpret intensity; much more sensory knowledge needed to protect face and head than trunk; sensory component discriminative, quick, and precise
Limbic system: where affect interpreted; separates humans from less developed species; allows reactions based on previous experience
Inhibition: occurs when central nervous system (CNS), (eg, periaqueductal gray area, opiate center, nucleus raphe magnus, serotonergic center, locus ceruleus, noradrenergic centers) modulates messages so they can be dealt with, allowing body to heal from stimulus
Nociception process: messages move through A-delta and C fibers, entering spinal cord or trigeminal system; here they divide into anatomic structures called Rexed laminae that enable identification of source and type of fiber; C fiber (unmyelinated) enters lamina II; A-delta fiber (lightly myelinated) enters laminae I and V; A-beta fiber (more proprioceptive and associated with inhibition of pain) enters lamina III; distribution highly important to understanding neuropathic pain; transduction — at peripheral ending, A-delta and C fibers release peptides such as substance P, calcitonin gene-related peptide (CGRP), and neurokinins; these peptides induce prostaglandin and other peripheral nociceptive stimulating agents to begin neurogenic inflammation; presents opportunities to modulate pain topically at periphery, inhibiting, eg, release of substance P with capsaicin, prostaglandins with anti-inflammatory agents, and neurokinins with steroids; descending control process — relied on after afferent input to sensory cortex and limbic system; powerful in humans; majority recover from injury in short time with no residual problems; 3% to 10% do not respond because of abnormality in neural system, leading to chronic neuropathic pain
Pain: IASP defines pain as “unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage”; does not require nociception, as pain is emotional experience, complicating interpretation
Acute pain: short or appropriate duration (usually <2 wk); specific pathology producing symptoms; treatment obvious; useful in getting person to physician; generally does not interfere with function
Chronic pain: duration of pain >6 mo by definition; longer than it should be, indicating system not working right; pathology often unclear; serves no useful purpose
Clinical pathway: patients with unclear pathology start on chronic pain pathway and see many physicians who offer different “right answers” but inadequate care; this leads to anxiety and depression; ≈45% of patients depressed and 45% have anxiety disorder by time they see specialist in chronic pain; speaker’s research on atypical facial pain after dental procedure — whereas literature suggested patients “crazy,” anxious, depressed women in 40s, speaker found only about 40% depressed and anxious (similar to any other chronic pain population)
Components of pain: nociception, pain behavior, suffering; once thought to occur in order, now seen as interlinking but potentially singular components; nociception can occur without pain behavior or suffering (eg, surgical patient under anesthesia); suffering possible without nociception or pain behavior; pain behavior can occur without nociception or suffering; differentiation allows physician to focus on most problematic component or treat each appropriately
Therapies for acute pain: surgery, medicine, immobilization (eg, broken limb), mobilization (eg, lumbar spine), anti-inflammatory agents, non-narcotic drugs, antinociceptive medications, narcotics, tranquilizers, steroids; most important — tender
loving care (reassuring bedside manner)
Characteristics of patients with chronic pain
Verbalization: pain becomes patient’s life, and patient describes it at length; clinician must learn to limit descriptions by asking specific questions in structured intake
Depression: can prevent patient’s ability to discriminate pain level on scale; treat depression first; Diagnostic and Statistical Manual (DSM)-III criteria — 4 criteria required for diagnosis of depression; change in appetite or weight, insomnia or hypersomnia, psychomotor agitation, loss of interest or pleasure, fatigue, feelings of worthlessness, decreased concentration, suicidal ideation; assessment — questionnaires (eg, Beck Depression Inventory), simple paper checklist, or oral interview
Hostility: many chronic pain patients present with anger, shouting, at wit’s end; clinician must set boundaries on hostile behaviors
Manipulativeness: often centered on obtaining narcotic medication; in speaker’s pain center, narcotic use highly structured (pain contract with patient, specific guidelines, no weekend refills); manipulativeness develops when patients become dependent on drug but cannot obtain refills
Drug abuse: usually not patients’ intent; patients do not start as abusers
Neuropathic pain: due to primary lesion or dysfunction in nervous system; pain signals received centrally disproportionate to stimulus experienced by patient; symptoms — usually constant pain, often dull, vise-like, superimposed with burning, shooting, stabbing pain; occasionally paroxysmal and electric-like in addition to burning; patients’ descriptions vary with their affective interpretation
Intermittent neuropathies: cranial neuralgias (trigeminal, glossopharyngeal, nervus intermedius); sharp electric jabs of pain lasting seconds to minutes
Continuous neuropathies: trigeminal dysesthesia or any dysesthesia after nerve injury; postherpetic neuralgia; complex regional pain syndrome (CRPS); diabetic neuropathy; poststroke neuropathies
Clinical signature of neuropathic pain: allodynia (increased response to non-noxious stimulus such as light touch, when compared with normal area); hyperalgesia (increased response to painful stimulus such as pinprick); hyperpathia (increased responses to same stimulus experienced repeatedly); pseudomotor abnormalities (mainly in limbs of patients with CRPS; temperature change in injured face); block effect (numbing of sensory nerve does not stop pain, indicating either central or autonomic involvement; sympathetic block often defines mechanism)
Populations at risk: women 40 to 49 yr of age — due mainly to estrogen; in animal and human studies, estrogen adversely affects nonopiate-mediated pain inhibition (through nucleus raphe magnus or locus ceruleus or dopamine), increasing susceptibility to nociception; postherpetic neuralgia — 10% incidence after herpes zoster; most patients over age 60 yr; limb amputation — 10% incidence of neuropathy; reduced to 3% if spinal block given before amputation; root canal and apicoectomy — 5% incidence (low due to local anesthesia at time of procedure); diabetic neuropathy — 12% incidence (small or large fiber); overall — about 10% of patients with nerve injury have neuropathy
Complex regional pain syndrome: diversity of painful conditions following trauma, coupled with sensory abnormalities, edema, autonomic dysfunction, motor symptoms, and trophic changes that can affect ≥1 areas of body; type I — formerly reflex sympathetic dystrophy; trauma not obvious; also known as sympathetically maintained pain, traumatic neuropathy, trigeminal dysesthesia; type II — also called causalgia; trauma obvious; mechanisms include peripheral sensitization; ectopic activity due to sodium channel expression; sympathetically maintained pain due α-receptor sprouting; small fiber neuropathy; central sensitization; beta-fiber reorganization; alteration in central inhibition; each provides target for therapeutic options
Pain mechanisms: peripheral sensitization — lingering pain from “soup” of inflammatory substances in periphery; ectopic activity after injury — nerve tries to regrow; nociceptive areas become more easily activated due to increased expression of sodium channels (allow depolarization of nerve); electric shooting pain blocked with sodium channel blockers (eg, carbamazepine, oxcarbazepine); sympathetically maintained pain — due to α-receptor sprouting caused by norepinephrine released from sympathetic system after injury; sympathetic block can stop pain; small-fiber neuropathy — spreading pain, skin hypersensitivity (allodynia), temperature change, osteopenia, edema, and sweating; skin biopsy shows decrease in protein gene product (PGP) and calcitonin gene-related peptide (CGRP) on nerve fiber; pain generated when destroyed fibers cause overactivation of neighboring A-delta and C fibers, triggering ectopic firing; can also activate glial cells (immune-mediated pain cells of CNS); evidence that skin biopsy can define peripheral neuropathy by showing loss of small fibers; central sensitization — after injury, cells of dorsal horn or trigeminal nucleus become sensitized by upregulation due to exposure to inflammatory substances; can create ongoing nociceptive drive just from dorsal horn; area numbed to address mechanism
Trigeminal neuralgia: not from traumatic injury; intermittent, shooting paroxysmal pain lasting from fraction of second to 2 min and affecting ≥1 divisions of trigeminal nerve; requires only light touch to trigger; caused by compression of trigeminal nerve by blood vessel (treated surgically with microvascular decompression; 95% efficacy); also caused by plaque in region of nerve, eg, in multiple sclerosis; mechanistically, compression causes opening of sodium channels in ganglion so pain easily triggered; sodium channel blockers effective
Mechanisms of chronic neuropathic pain: N-methyl-d-aspartate (NMDA) — after injury, C fibers send message to NMDA receptors, but receptors blocked by magnesium plug; barrage of nociception required; glutamate binds first to NMDA receptors; process pushes plug out of NMDA so glutamate can bind, activating synthesis of nitric oxide (NO); NO destroys pain-inhibiting neurons permanently; in animal model, NMDA antagonists prevent neuropathic pain, but antagonists also hallucinogenic; ketamine and dextromethorphan therapeutic options (but must be used before injury); A-beta fiber reorganization — C fiber enters lamina II, but if destroyed, it dies away, and A-beta fiber grows into lamina II; temperature and touch can now trigger pain; reorganization irreversible; abnormality in central inhibition — pain not blocked because of abnormality in descending control; research using functional magnetic resonance imaging (fMRI) has found specific “pain matrix” that responds to affective and sensory messages of pain but responds differently to relief of pain; future drug testing can investigate changes in matrix and parts of brain that indicate relief; revolution in understanding that brain itself must create specific message to switch off pain
Immune-mediated pain: involved in body pain associated with infection; Watkins et al theorize that macrophages activated by infection release proinflammatory cytokine interleukin-6 (IL-6), leading to stimulation of vagus nerve and sending of nociceptive response to lamina or creating pain signal; pain necessary to cause body to lie still and raise temperature to fight infection; if IL-6 blocked or vagus nerve cut in animal model of infection, no pain occurs; IL-10 in brain completely inhibits IL-6, IL-1, and tumor necrosis factor (TNF)-α; IL-10 analogues under study to treat virally-mediated neuropathies
Mirror-image pain: if infection damages nerve in one limb, release of proinflammatory cytokines can produce pain in opposite limb; only mechanism described to cause mirror image pain; AV-411 (drug being evaluated in Japan) can block nerve pain; also blocks withdrawal from narcotics
Migraine mechanisms: genetic predisposition — brain must be genetically predisposed to triggering by variety of stimuli, eg, drop in estrogen, change in barometric pressure, foods, stress; migraine generator — area in brain seen on fMRI; when activated, patient experiences nociception or pain; pain secondary to neural inflammation activated after aura (due to depolarization of brain); nociceptive responses — first division of trigeminal nerve releases neural sensitizers around peripheral lining of brain, causing secondary vasodilation (not cause of migraine); triptan medications bind to receptors on nerve and blood vessel, stopping release of peptides, thus stopping pain; if message reenters CNS, can reactivate second-order neurons, glial cell function, and central sensitization, resulting in allodynia (whole body pain); thus triptans should be used as early as possible; sinus-like headache — ≈45% of patients with migraine have engorgement within nasal cavity and stuffiness in face; sinus pathology involves second-division activation; neck pain — results from interaction between C1, C2, and C3 with trigeminal nucleus; neck pain aborted with triptan medications
Pharmacologic targets of nociceptively driven disorders: periphery — local anesthesia, cyclooxygenase (COX)-2 inhibitors, traditional nonsteroidal agents, sodium channel blockers, and topical effects of tricyclic antidepressants (TCAs); neural blockade — sympathetic vs somatic block; reversal of central sensitization — opioids, α2-agonists, NMDA antagonists, sodium and calcium channel blockers; CNS — α2-agonists, β-blockers, centrally-acting analgesics, COX-2 inhibitors, traditional nonsteroidal agents, TCAs, serotonin and norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs); affective component — addressing serotonergic systems, dopaminergic systems, norepinephrine, ϒ-aminobutyric acid (GABA), and glutamate through limbic function useful when behavioral factors present; antidepressants and SNRIs most effective for neuropathic pain; antiepileptic agents; nonsteroidal agents; muscle relaxants; migraine — nonspecific analgesics; migraine-specific analgesics; prophylaxis through TCAs, SNRIs, cardiovascular agents, blood vessel agents, neural stabilizers such as topiramate, and gabapentin; botulinum toxin
Conclusion: Every patient unique with own brain and personality; must treat whole patient, not just nerve, joint, or muscle
Dr. Graff-Radford spoke at Current Concepts and Challenges in the Management of Pain, presented March 23, 2013, in Los Angeles, CA, and sponsored by Cedars-Sinai Pain Center . For more information about upcoming CME activities from this sponsor, please visit http://www.Cedars-Sinai.edu/Medical-Professionals/Continuing-Medical-Education/CME-Courses. The Audio-Digest Foundation thanks Dr. Graff-Radford and the Cedars-Sinai Pain Center for their cooperation in the production of this program.
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