The following is an abstracted summary, not a verbatim transcript, of the lectures/discussions on this audio program. If, after reviewing this written summary, you would like to hear the contents and/or earn CME/CE credit, simply visit the Audio-Digest Foundation website
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The goal of this program is to improve the management of chronic pain conditions. After hearing and assimilating this program, the clinician will be better able to:
1. Appreciate pathophysiologic distinctions between acute and chronic pain.
2. Identify factors that predispose patients to developing chronic widespread pain and central pain.
3. Restore proper modulation of nociceptive signaling to relieve pain in patients with central pain.
4. Explain pain-reducing mechanisms associated with different psychotropic adjuvants for pain.
5. Provide adjuvants to relieve pain in treatment-resistant patients.
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. Clauw is a consultant for AstraZeneca, Cypress Bioscience, Eli Lilly, Forest Laboratories, Pfizer, Pierre Fabre, and UCB; he also receives research support from Cypress Bioscience, Forest Laboratories, and Pfizer. Dr. Cole is on the Speakers’ Bureau for Eli Lilly, on the Advisory Board for Eli Lilly and Purdue Pharma, has stock in Johnson & Johnson, and is an employee of Aventine Co. The planning committee reported nothing to disclose. In their lectures, Drs. Clauw and Cole present information that is related to the off-label or investigational use of a therapy, product, or device.
Dr. Clauw was recorded at 21st Annual Advances in Psychiatry, held November 5-6, 2009, in Ann Arbor, MI, and sponsored by the University of Michigan Medical School, the University of Michigan Medical School Department of Psychiatry, University of Michigan Depression Center, Michigan Psychiatric Society, Depression and Bipolar Alliance, VA Ann Arbor Healthcare System, Michigan National Guard, and Quality Improvement for Complex Chronic Conditions. Dr. Cole was recorded at 15th Annual Psychopharmacology Update, held February 11-13, 2010, in Las Vegas, NV, and sponsored by the Nevada Psychiatric Association, and the University of Nevada School of Medicine. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
Daniel J. Clauw, MD, Professor of Anesthesiology, Medicine, and Psychiatry, Director, Chronic Pain and Fatigue Research Center, and Director, Michigan Institute for Clinical and Health Research, University of Michigan Medical School, Ann Arbor
Chronic pain: speaker argues new knowledge invalidates current treatment paradigms; classified as disease, and, as such, region of pain often irrelevant; mechanisms of chronic and acute pain differ; in chronic pain states, damage and inflammation to peripheral tissues cannot accurately predict subjective pain; studies consistently show poor correlation between chronic pain states (eg, angina) and condition of peripheral tissues; osteoarthritis — in patients ³60 yr of age, 30% to 40% of those with most severe arthritis on radiography report no pain; 20% of patients with most severe pain have normal radiography; psychiatric factors — often incorrectly cited by physicians as cause of pain symptoms in absence of peripheral findings; in reality, explain only minor variations in presentation; recent findings — conditions such as fibromyalgia (FM), irritable bowel syndrome (IBS), and idiopathic low back pain (LBP) appear related to poor modulation of pain sensing and transmission in brain and spinal cord
Peripheral pain (PP): acute and chronic pain caused by local inflammation and nociception respond to acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids; PP often improves with surgery when medications fail; classic peripheral or nociceptive pain states — acute pain due to injury; osteoarthritis; rheumatoid arthritis; cancer pain; neuropathic pain (NP) — relatively uncommon; eg, diabetic NP, postherpetic neuralgia (PHN)
Central or non-nociceptive pain states: characterized by disturbance of pain processing in brain and spinal cord; effective medications alter levels of neurotransmitters involved in pain or sensory processing; classic examples — FM; IBS; temporomandibular joint disorder; tension headache; comorbidity — 20% to 30% of patients with nociceptive pain have concurrent or comorbid central pain; identify patients with PP causing hyperalgesic states; patients with comorbid central pain require treatment for both PP and central pain; NP responds to NSAIDs, opioids, and neuroactive agents (eg, tricyclic antidepressants [TCAs], serotonin-norepinephrine reuptake inhibitors [SNRIs], a-2-δ ligands); central pain often comorbid with psychiatric disorders; sensory amplification — major biologic factor in FM; occurs in large subset of individuals with regional pain states
Identifying central pain: somatic symptoms — almost universally accompany central pain; eg, fatigue, insomnia, memory problems; often occur without identifiable psychiatric cause; multifocal pain — history of many pain sites or pain types increases likelihood of central pain
Fibromyalgia: prevalence 1.5 to 2-fold greater in women; however, speaker argues FM not exclusive to women; diagnosis —in studies, men rarely found to have >11 tender points; diagnostic criteria requiring large number of tender points therefore inaccurate in men; speaker recommends diagnosing FM based on presence of chronic widespread pain and somatic symptoms; new diagnostic criteria — no tender point examination required; instead, relies on multifocal pain in >6 regions on regional pain diagram and presence of somatic symptoms or syndromes; based entirely on self-reporting (as in diagnosis of other chronic pain states)
Pathophysiology: evidence indicates strong familial or genetic component; stressors capable of triggering depression or posttraumatic stress disorder may trigger pain; neurologic causes — regional issues with serotonin or norepinephrine concentrations in amygdala may cause depression only, whereas global abnormalities involving neurotransmitters may affect regions of brain responsible for pain processing as well as mood; may explain high cormorbidity between pain and psychiatric conditions; features —sensory amplification (most reproducible); autonomic nervous system dysfunction; hypothalamic-pituitary-adrenal axis dysfunction; neurogenic inflammation
Role of stress: early-life stressors — potent trigger in many chronic pain states; United Kingdom study — patients with history of prolonged hospitalization or involvement in motor vehicle collisions at 8 yr of age had 1.5-fold higher rate of chronic widespread pain in adulthood; PP syndromes — may cause central pain; triggers — physical trauma; catastrophic events; infection; infectious causes — regions with infection show predisposition to chronic pain; 5% to 10% of patients with documented Salmonella, Shigella, or Campylobacter infections develop IBS; after infection clears, chronic pain in abdominal region or IBS often persists; 5% to 7% of adults with Epstein-Barr virus, Lyme disease, or parvovirus infections develop FM or chronic fatigue syndrome; genetic factors probably determine risk for residual pain states after infection; speaker’s study — exposure to World Trade Center attacks had no effect on pain levels (explained by social support and sense of control); daily interpersonal stressors associated with worsening or triggering pain
Findings: in general population, poor response to pain testing predicts risk for development of chronic pain over several years; dysfunctional neurologic “volume control” or “gain setting” —associated with high levels of neurotransmitters involved in pain and sensory transmission (eg, substance P, glutamate, nerve growth factor [NGF]) and low levels of, norepinephrine, serotonin, dopamine, endogenous opioids, g-aminobutyric acid (GABA), and endocannabinoids; blocking elevated neurotransmitters or boosting suppressed neurotransmitters can treat hyperalgesic or allodynic states; FM — brain and spinal fluid show 2- to 3-fold increases in substance P and NGF and 2-fold increase in glutamate; spinal fluid shows decreases in metabolites of norepinephrine, serotonin, and dopamine; opioidergic systems show hyperactivity (eg, high levels of endorphins and enkephalins) and decreases in available μ-opioid receptors; high levels of endogenous opioids may explain poor efficacy of opioid medications; “essential hypertension” of pain processing pathways — imbalances in various combinations of neurotransmitters may trigger common pain pathway involved in development of chronic pain; due to varying etiologies, medications effective in only 35% to 40% of patients with FM; medications that antagonize receptors for substance P, glutamate, and NGF lacking (thus, nonpharmacologic therapies often required)
Processing of pain: 3 independent regions involved in pain; sensory processing — ie, location and duration of pain; largely occurs in primary and secondary somatosensory cortices, thalamus, and posterior insula; affective processing — ie, emotional valence; largely occurs in anterior cingulate cortex, anterior insula, and amygdala; highly selective serotonin reuptake inhibitors (SSRIs; eg, citalopram, escitalopram) may reduce depression by altering affective processing of pain, but sensory processing remains unaffected; increasing both serotonin and norepinephrine required for analgesic effects
Functional magnetic resonance imaging: in studies, patients with FM processed low-intensity stimulus as high-intensity stimulus; pain and depression — strikingly independent; some medications have both analgesic and antidepressant effects (eg, duloxetine, milnacipran); however, depressed and nondepressed patients receive equal pain benefits when given TCAs or SNRIs; cognition —patient’s thought patterns about pain may affect neurologic volume control; input from cortical centers (eg, dorsolateral prefrontal cortex) affects regulatory regions lower in brain
Global defects in sensory processing: recent studies suggest role in causation of chronic pain; patients with chronic pain often report sensitivity to bright lights, loud noises, and unpleasant odors; insular cortex — integrates all sensory information (including interoception); consistently hyperactive in imaging studies of patients with FM and hyperalgesic states; somatization may be caused by abnormal neurotransmitter levels in insula and other pain processing regions; study found patients with FM show increased levels of glutamate in insula; changes in glutamate levels over time correlate with changes in clinical and experimental pain; dorsal horn gateway — prevents nociceptive signaling from reaching brain; normally remains closed due to tonic inhibition by descending opioidergic, serotonergic, and noradrenergic pathways from periaqueductal gray and locus ceruleus; however, two-thirds of patients with IBS or FM lack descending analgesic pathways (particularly serotonergic and noradrenergic), and thus lack filtering of PP signals
Pharmacologic treatments: TCAs — speaker prefers cyclobenzaprine (5-15 mg, 2 hr before bedtime); SNRIs —milnacipran and duloxetine currently approved for FM; associated with nausea during first 7 to 10 days of treatment (warn patients); a-2-δ ligands — eg, pregabalin; gabapentin; two-thirds to entire dose before bedtime improves tolerability; agents with modest evidence — tramadol; older SSRIs (eg, sertraline, paroxetine, fluoxetine); older SSRIs — show noradrenergic reuptake inhibition at higher dosages; in study using average dose of 45 mg, fluoxetine showed significant efficacy as analgesic for FM (not seen at lower doses); g-hydroxybutyric acid —may be approved for FM; thought to increase GABA; dopamine agonists —show some utility; opioids — use strongly discouraged by speaker; may exacerbate hyperalgesia or cause opioid-induced hyperalgesia
Psychologic treatment: addresses consequences of long-term chronic pain (eg, distress due to lack of normal functioning, psychiatric comorbidities, maladaptive behavior, catastrophizing, external locus of pain control [ie, helplessness]); pain and fatigue — cause functional problems (eg, distress, decreased activity, isolation, poor sleep, maladaptive behavior); produced by even mild short-term restrictions of exercise or sleep in 50% of healthy patients; treatments backed by strong evidence — education; aerobic exercise; cognitive behavioral therapy; use of supportive website (www.nofibro.com) shown to improve FM more than any approved medication
Psychotropic Adjuvant Medications for Managing Pain
Barry Eliot Cole, MD, MPA, CPE, Executive Director, American Society of Pain Educators, Montclair, NJ
Pharmacology: SSRIs — ineffective for chronic pain; alleviate depression in patients with chronic pain (comorbid in 50%); opioids — patients with chronic pain have neurons with reversed noradrenaline and serotonin activity; opioids normalize neurotransmitter functioning in affected cells; regions involved in chronic pain predominantly noradrenergic and serotonergic; serotonin — facilitates both exacerbation and inhibition of pain (depending on receptor type); noradrenaline — universally inhibits pain; TCAs — affect both serotonin and noradrenaline; show limited effects in adrenergic systems and sodium channels (amitriptyline induces anesthesia when injected peripherally); antagonizes histamine, substance P, and N-methyl-D-aspartic acid (NMDA) systems; relief of depression not required to relieve pain; typically contraindicated for patients ³60 yr of age; all TCAs show efficacy for NP (recommended as first-line treatment); often recommended for cancer pain; monoamine oxidase inhibitors — not recommended due to issues with efficacy and compliance
Neuropathic pain: easy to study because overtly manifested (eg, shows positive and negative symptoms; correlated with electromyography and nerve conduction velocity tests); superior pain models evaluate chronic pain with NP models; mirtazapine — noradronergic activity seen at higher doses; venlafaxine and desvenlafaxine — literature shows efficacy for NP; SSRIs — high doses of paroxetine (60 mg daily) show efficacy for NP; generally ineffective for pain relief (due to absence of necessary noradrenergic effects); SNRIs — reduce overdose potential and cholinergic side effects associated with TCAs; duloxetine and milnacipran indicated for painful disorders (eg, FM, diabetic peripheral NP); mechanism of action (MOA) — differs among medications; effects range from transduction in peripheral nerves to areas deep within brain; studies show significant efficacy of TCAs in diabetic NP, PHN, and FM, but less so in trigeminal neuralgia (TN), central pain, and headaches; venlafaxine and duloxetine recommended for NP; duloxetine recommended for FM; medication rotation often necessary
Antiepileptic drugs (AEDs): MOA involves modulation of sodium and calcium channels, GABA effects, and blocking NMDA activity; AEDs limit signaling between peripheral nerves and dorsal horn; carbamazepine, oxcarbamazepine, gabapentin, and pregabalin show potential (speaker recommends pregabalin)
Anxiolytics: treat symptoms not directly related to pain; in some patients, judicious use of anxiolytics may be vital for pain control or even superior to analgesic escalation; show benefits in acute situations; not recommended for chronic nonmalignant persistent pain; benzodiazepines — pain literature recommends benzodiazepines with longer half-lives; however, psychiatric literature recommends short-acting agents; indicated for TN; combines musculoskeletal relaxation with sedative-hypnotic effects; no independent effect on pain; TN — NP condition; agents with antiseizure effects (eg, clonazepam) control NP condition; speaker’s recommendations — use anxiolytics for affective distress, hyperviligence, and suffering associated with pain
Other agents: antipsychotics — no longer used by pain specialists; atypical antipsychotics — olanzapine supported by limited hospice literature; not recommended by speaker; stimulants — reverse opioid-induced sedation
Number needed to treat (NNT): TCAs show superior efficacy (NNT 4; however, approaches 1.8 when used with blood level testing); SNRIs, 5; gabapentin and pregabalin, »4; opioids, 2.5 to 3; tramadol, 3.5 to 5; tapentadol efficacy remains unclear (derivative of tramadol; μ-opioid agonist and noradrenaline reuptake inhibitor; useful for acute pain); topical lidocaine, 4
Treatment-resistant patients: patients failing to respond toone opioid may benefit from another (due to different receptor profiles); addition of gabapentin or pregabalin or antidepressants recommended
General principles of adjuvant therapy: do not titrate medications simultaneously; start at low doses and escalate slowly; adjuvants may radically modulate other medications if cytochrome P450 system affected (expect both additive side effects and changes in side effect profiles); high degree of customization involved, so treatment takes weeks to months; diagnoses may require many different treatments; consider effects of psychopharmacology on all prescriptions; give effective doses for sufficient periods of time; watch and monitor for adverse side effects; use adjuvants to treat mechanisms of pain; in patients with depression and chronic pain, relief from depression does not affect pain
Arnold LM et al: Flexible dosed duloxetine in the treatment of fibromyalgia. J Rheumatol 37:2578; Canavero S, Bonicalzi V: Central pain syndrome: elucidation of genesis and treatment. Expert Rev Neurother 7:1485, 2007; Cole BE: Neuroendocrine implications of opioid therapy. Curr Pain Headache Rep 11:89, 2007; Finnerup NB et al: The evidence for pharmacological treatment of neuropathic pain. Pain 150:573, 2010; Finnerup NB, Jensen TS: Clinical use of pregabalin in the management of central neuropathic pain. Neuropsychiatr Dis Treat 3:885, 2007; Gore M et al: Initial use of pregabalin, patterns of pain-related pharmacotherapy, and healthcare resource use among older patients with fibromyalgia. Am J Manag Care 16:S144, 2010; Mease P et al: Fibromyalgia syndrome. J Rheumatol 34:1415, 2007; Peterson DL et al: Central amplification and fibromyalgia: disorder of pain processing. J Neurosci Res 89:29, 2011; Unger J, Cole BE: Recognition and management of diabetic neuropathy. Prim Care 34:878, 2007; Wasner G: Central pain syndromes. Curr Pain Headache Rep 14:489, 2010.