Chronic Pain · Director, Comprehensive Pain Program Albany Medical Center Albany, New York Bill H. McCarberg, MD Founder Chronic Pain Management Program Kaiser Permanente Escondido,

Made possible by an educational grant from Eli Lilly and Company

Chronic Pain In Perspective

Recent Evidence andClinical Implications

Jointly sponsored by thePostgraduate Institutefor Medicine and Applied Clinical Education

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Disclaimer

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activ-ity should not be used by clinicians without evaluation of their patient’s conditions, possible contraindications or dangers with use, review of applicable manufacturer’s product information, and comparison with recommendations of other authorities.

Faculty

Charles E. Argoff, MD

Professor of NeurologyAlbany Medical CollegeDirector, Comprehensive Pain ProgramAlbany Medical CenterAlbany, New York

Bill H. McCarberg, MD

FounderChronic Pain Management ProgramKaiser PermanenteEscondido, CaliforniaAdjunct Assistant Clinical ProfessorUniversity of California, San DiegoSan Diego, California

Release Date: November 1, 2009 Expiration Date: November 30, 2010

Estimated Time To Complete This Activity: 1 hour

Target AudienceThis activity has been designed to meet the educational

needs of clinicians working in the area of pain management.

GoalThe goal of this activity is to educate primary care physicians

and pain specialists about clinically diverse pain manifestations and chronic pain mechanisms, particularly with regard to evi-dence-based selection and use of current and emerging phar-macologic treatment strategies.

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Statement of Need

Chronic pain affects approximately 10% to 20% of patients in primary care. Among the most common chronic pain condi-tions are low back pain, osteoarthritis, fibromyalgia, and dia-betic peripheral neuro pathic pain. Morbidity in chronic pain is high, including lower quality of life and increased fatigue, and comorbidities are common, including depression, anxiety, and sleep disturbances. The costs to society in lost productivity and increased health care utilization are great. Thorough assess-ment is needed to determine the best approach to managing a patient with chronic pain, along with careful consideration of pharmacologic and nonpharmacologic treatment options. These tasks have become more complex as the pathophysiol-ogy of pain has become better understood, new therapies have become available, and new guidelines have been published. Clinical education is needed to guide clinicians in assessing and managing patients with chronic pain so that therapeutic outcomes are improved.

Educational ObjectivesAt the completion of this educational curriculum, participants

should be better prepared to:Describe pathophysiologic mechanisms that have been pro-1. posed for prevalent chronic pain conditions (low back pain, osteoarthritis, fibromyalgia, and diabetic peripheral neuro-pathic pain).Restate the rationale for initial and ongoing evaluation of 2. chronic pain and restoration of function.Summarize available primary and consensus evidence on opti-3. mal nonpharmacologic and pharmacologic treatment strate-gies for management of prevalent chronic pain conditions.Discuss evidence-based strategies for the use of first-, sec-4. ond-, and third-line pharmacotherapy options for chronic pain.

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Accreditation Statement

This activity has been planned and implemented in accor-dance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the sponsorship of Postgraduate Institute for Medicine (PIM) and Applied Clinical Education. PIM is accredited by the ACCME to provide continuing medical education for physicians.

Credit DesignationPostgraduate Institute for Medicine designates this edu-

cational activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Disclosure of Conflicts of InterestPostgraduate Institute for Medicine assesses conflicts of

interest with instructors, planners, managers, and other individu-als who are in a position to control the content of CME activities. All relevant conflicts of interest that are identified are vetted thoroughly by PIM for fair balance, scientific objectivity of stud-ies referenced, and patient care recommendations. PIM is com-mitted to providing learners with high-quality CME activities and related materials that promote improvements in health care and not a specific proprietary commercial interest.

The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity:

Dr. Argoff: Eli Lilly, Endo, Forest, King, Pfizer, Pricara (consul-tant, speakers’ bureaus); Nicox, Registrat, UCB, Vertex (consul-tant); Endo (research).

Dr. McCarberg: Abbott, Cephalon, Endo, Forest, King, Ligand, Lilly, Merck, Mylan, Pfizer, Pricara, Purdue (speakers’ bureaus).

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The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity:

Linda Graham, RN, BSN, BA; Jan Hixon, RN, BSN, MA; Trace Hutchison, PharmD; Julia Kirkwood, RN, BSN; Samantha Matti-ucci, PharmD; and Jan Schultz, RN, MSN, CCMEP; PIM: none.

George Ochoa and Jennifer Kulpa, medical writers: none.

Method of ParticipationThere are no fees for participating in and receiving CME credit

for this activity. During the period November 1, 2009 through November 30, 2010, participants must 1) read the learning objec-tives and faculty disclosures; 2) study the educational activity; 3) complete the post-test by recording the best answer to each question in the answer key on the evaluation form; 4) complete the evaluation form; and 5) mail or fax the evaluation form with answer key to PIM. Statements of credit will be mailed to participants within 3 weeks of faxed or mailed submissions. The post-test also may be completed online at www.cmeuniversity.com (click on “Find Post-Test/Evaluation by Course” in the navigation menu; search by Project ID 6759) and www.CMEZone.com (availability may be delayed from original print date; enter project code PG0923 in the keyword field). A statement of credit will be made available immediately upon suc-cessful completion of the post-test and evaluation. A score of 70% or better is required to complete the post-test successfully.

Media: Journal supplement

Disclosure of Unlabeled UseThis educational activity may contain discussion of published

and/or investigational uses of agents that are not indicated by the FDA. PIM, Applied Clinical Education, and Eli Lilly and Com-pany do not recommend the use of any agent outside of the labeled indications.

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The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of PIM, Applied Clinical Education, and Eli Lilly and Company. Please refer to the official prescribing information for each product for discus-sion of approved indications, contraindications, and warnings.

Copyright © 2009 Postgraduate Institute for Medicine and Applied Clinical Education. All rights reserved. No part of this monograph may be used or reproduced in any manner whatso-ever without written permission except in the case of brief quo-tations used in articles or reviews.

Jointly sponsored by the Postgraduate Institute for Medicine and Applied Clinical Education.

Made possible by an educational grant from Eli Lilly and Company.

Distributed by

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Introduction ��10

Pathophysiology ��12Figure� Pain types and their

proposed mechanisms ��13

Assessment and Diagnosis ��15Table 1� Examples of Validated

Pain Assessment Tools ��18

General Principles in the Management of Chronic Pain��19

Table 2� Current Treatment Approaches to Selected Chronic Pain Conditions ��20-24

Nonpharmacologic Treatment ��26

Pharmacologic Treatment �� 26Table 3� Selected Pharmacologic Agents

for Chronic Pain ��28-37

Conclusion ��40

References ��41-48

CME FormsPost-Test ��49-50

Evaluation Form �� 51-53

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Table of Contents

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Introduction

Pain is defined as an unpleasant sensory and emotional experience caused by noxious sensory stimuli accompa-nying actual or potential tissue damage.1 A complex phe-

nomenon, pain includes cognitive and emotional components.2,3 Acute pain is adaptive, contributing to survival by protecting the individual from injury or promoting healing.4 Chronic or persis-tent pain, however, persists beyond an expected healing time or beyond a designated time period, often identified as 3 months, is maladaptive, and serves no useful function.3,4 Chronic pain also may represent a state in which the nervous system has been altered to facilitate enhanced pain signaling.

Clinically meaningful chronic pain is a reality for a significant number of individuals. A recent study analyzing data from more than 10,000 responders to a US-based survey found that 11% of subjects described chronic localized pain, and 4% described chronic widespread pain.5 Furthermore, approximately 10% to 20% of patients seen in primary care practices report chronic pain.6 Numerous clinical conditions are associated with chronic pain, typically identified by the site of injury (eg, low back, carpal tunnel, head, neck, viscera) or type of injury (eg, arthritic, cancer, diabetic, myofascial, neuropathic).7 Among the most common is chronic low back pain (LBP), which has an annual prevalence



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rate of 15% to 45%.7 Osteoarthritis (OA) affects nearly 27 mil-lion US adults, and fibromyalgia (FM) affects 5 million.8 Diabetic peripheral neuropathic pain (DPNP; also sometimes referred to as neuropathic pain associated with diabetic peripheral neurop-athy [DPN]) is less common; among the 20.8 million people esti-mated to have diabetes mellitus, approximately 50% have DPN, and 11% of that group experience neuropathic pain associated with the condition.9

Chronic pain is associated with significant morbidity. Patients with chronic pain often have lower quality of life (QoL)10 and greater fatigue11 than their healthier cohorts. Chronic pain is independently related to low self-rated health,12 and having one chronic pain syndrome is associated with a higher than expected likelihood of having another.13 In addition, psychiatric comorbidi-ties are common.14 FM, for example, frequently is comorbid with depression, panic disorders, anxiety, and post-traumatic stress disorder,15 conditions that may lead to even greater morbidity. Delays in treatment are particularly damaging: In a systematic review, patients with chronic pain who had to wait 6 months from the time of referral until treatment had significant deterioration in health-related QoL and psychological well-being.16 In older adults, these issues are especially common,17 as undertreated pain can lead to reduced QoL, decreased socialization, depression, and sleep disturbances.18 Higher levels of comorbidity are associated with reports of more severe pain, more depressive symptoms, reduced activity, and greater physical impact from pain.19

Chronic pain exacts a high cost from society through lost productivity among actively employed individuals. Such costs are estimated at $61.2 billion per year.20 In a compari-son of 2005 health care resources used by matched sam-ples of employees with FM, employees with OA, and controls, total costs for employees with FM were $10,199 and with OA were $10,861—significantly higher than for controls ($5,274; P<0.0001).21 Whereas absenteeism is a well-known negative

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effect of chronic pain and other chronic illnesses,21,22 presentee-ism also is important. In a study using the Stanford Presenteeism Scale to assess the costs of at-work impairment among employ-ees at a major US corporation, the most common interfering health conditions were allergies, arthritis/joint pain or stiffness, and back or neck disorders. Decreases in on-the-job functioning due to these conditions ranged from 17.8% to 36.4%, and the overall costs linked to presenteeism exceeded those of absen-teeism and medical treatment combined.23

With the goal of helping clinicians improve outcomes for patients with chronic pain, this monograph will address the pathophysiology, assessment and diagnosis, and management of chronic pain conditions, with particular attention to musculo-skeletal pain disorders causing both nociceptive and inflamma-tory pain, neuropathic pain disorders, and pain associated with central nervous system augmentation.

PathophysiologyFour main types of pain have been conceptualized (Figure).4

Pain thresholds vary depending on the pain type and may be viewed on a spectrum from higher to lower, as shown.4 Pro-posed mechanisms for these types of pain will be summarized in the section below.

Nociceptive pain • is transient and occurs in response to a normally noxious stimulus such as a burn or cut.4,24 It occurs via activation of the nociceptive system, which extends from peripheral tissue through the spinal cord, brain stem, and thalamus to the cerebral cortex, where the pain ultimately is perceived.4 Inflammatory pain• is spontaneous pain as well as hyper-sensitivity to pain in response to tissue damage and inflam-mation, such as in rheumatoid arthritis (RA). Inflammatory mechanisms play an important role in sensitizing nocicep-tive structures and may lower pain thresholds.4

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Brain

Brain

Brain

Brain

Chemicalirritants

Normal peripheraltissue and nerves

Nociceptive pain (Example: acute postoperative pain)

Inflammatory pain (Examples: active RA, acute OA flare)

Neuropathic pain (Examples: DPNP, PHN)

Pain associated with central augmentation (Example: fibromyalgia)

Pain Autonomic responseWithdrawal reflex

Spinal cord

Spinal cord

Spinal cord injury

Abnormal central processing

Spontaneous painPain hypersensitivity • Reduced threshold:

allodynia • Increased response:

hyperalgesia

Spontaneous pain Pain hypersensitivity • Reduced threshold:


hyperalgesia

Spontaneous pain Pain hypersensitivity • Reduced threshold:


hyperalgesia

Stroke

Peripheral nervedamage

Noxious peripheral stimuli

HeatCold

Intensemechanical

force

Inflammation

Macrophage

Mast cell

Neutrophilgranulocyte

Tissue damage Nociceptorsensory neuron

Nociceptorsensory neuron

Figure. Pain typesa and their proposed mechanisms.4

DPNP, diabetic peripheral neuropathic pain; OA, osteoarthritis; PHN, postherpetic neuralgia; RA, rheumatoid arthritis a Increasingly, many chronic pain conditions such as low back pain and OA are viewed as having features of more than one of these pain types� Annals of Internal Medicine by Clifford Woolf� Copyright © 2004 American College of Physicians - Journals� Reproduced with permission of American College of Physicians�

High

LowPain

Threshold

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Neuropathic pain,• such as that associated with DPN, is spontaneous pain as well as hypersensitivity to pain in response to dysfunction or a lesion of the central or periph-eral nervous system. This type of pain is associated with lower-than-expected pain thresholds such as may be dem-onstrated in allodynia (pain upon receiving a normally non-painful stimulus).4 Pain associated with central augmentation,• such as in FM, is hypersensitivity to pain resulting from augmented central processing of normal input. This type of pain also is associated with a lowered pain threshold.4,25 Many chronic pain syndromes include more than one type of

pain; for example, OA includes both nociceptive and inflamma-tory pain,26 and LBP can include both nociceptive axial and neuro-pathic radicular pain.27

Mechanisms of Pain

Different mechanisms of pain have been hypothesized. In nociception—the mechanism that produces nociceptive pain—a noxious stimulus is converted into electrical activity in periph-eral terminals of nociceptors (transduction), conducted to the central terminals of nociceptors (conduction), transmitted from one neuron to another (transmission), and perceived in the brain as pain (perception). Peripheral sensitization refers to a reduction in threshold and rise in responsiveness of the peripheral ends of nociceptors.4,28 It is caused by the action of inflammatory medi-ators and activated inflammatory cells. For example, the enzyme cyclooxy genase-2 (COX-2), induced in response to interleukin-1β and tumor necrosis factor-α, produces the sensitizing agent pros-taglandin E2. Central sensitization contributes to inflammatory, neuropathic, and centrally augmented pain.4 In addition to periph-eral sensitization, central sensitization is one of the 2 major causes of hypersensitivity to pain after injury. In central sensitization, the strength of the synaptic connections between nociceptors and

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neurons within the central nervous system is altered, increasing transmission of pain.4,28

Other mechanisms of pain include augmented facilitation, in which facilitatory descending influences exerted by the brain are augmented, contributing to the increase in pain after inflammation or peripheral nerve injury.4 In decreased inhibition, loss of descend-ing inhibitory inputs from the brain stem, which operate through nor-epinephrine and serotonin, may contribute to neuropathic pain. In ectopic excitability, ectopic impulses are generated without periph-eral stimulus, contributing to spontaneous neuropathic pain. In phe-notype switch, the chemical character of the neuron is changed, making it hyperresponsive. In neuron-glial interaction, microglia in the spinal cord, in response to peripheral nerve injury, act on neurons and their supporting glia to alter their properties and contribute to pain hypersensitivity.4,29 In structural reorganization, structural rewir-ing of the connectivity of the spinal cord may induce heightened sensitivity to pain in patients with neuropathic pain.4 One or more mechanisms may underlie an individual’s chronic pain.

Assessment and DiagnosisIn determining an accurate diagnosis of a chronic pain disorder, a

comprehensive assessment is essential. Such an assessment must reflect the multidimensional nature of chronic pain as a biopsychoso-cial phenomenon by taking into account all 3 of those dimensions—biological, psychological, and social.14 Although understanding the underlying pain etiology is important, an exclusively physiologic per-spective of a chronic pain condition can omit important domains of a patient’s pain experience, such as potential comorbid depression or impaired ability to perform activities of daily living, thus nega-tively affecting treatment outcomes. With the biopsychosocial per-spective in mind, the clinician should assess and document specific factors including pain location, intensity, quality, temporal character-istics, and effects (eg, on function, sleep, mood, work); how pain is expressed; and what relieves or worsens pain.30,31

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Temporal characteristics may be particularly important in an assessment of pain.30 For example, a patient may have increased pain intensity and stiffness in the morning; on days during which greater feelings of depression are experienced; or in the eve-ning, after an especially active day. Pain levels also may fluctu-ate throughout the day, making an assessment tool such as the daily pain diary—on which an individual plots pain intensity lev-els on an hourly grid—a useful method of identifying patterns and potential treatment strategies for pain.

Brief, periodic fluctuations in pain severity may occur against the backdrop of otherwise generally well-controlled chronic pain. Characterized as breakthrough pain (BTP), these episodes are believed to be a common component of many chronic pain con-ditions and are described as transitory, more severe than the underlying pain, and as negatively affecting patient function and QoL.32,33 Three types of BTP have been identified:32,33

Precipitated or incident BTP is associated with an identifiable 1. stimulus such as physical activity or sudden movement.Idiopathic BTP occurs independently of an identifiable 2. stimulus.End-of-dose failure occurs regularly at the end of an analge-3. sic dosing cycle. BTP should be assessed as separate from the underlying pain

condition and treated accordingly, as each type may portend the need for adjustment in the treatment regimen.32,33,34

As is true for any medical assessment, a general history and physical examination are necessary in cases of chronic pain.30 The history should include an account of the pain condition from initiation to present, as well as a detailed discussion of previ-ous treatments—both pharmacologic and nonpharmacologic—and associated benefits and adverse events (AEs).31,35 Duration and dosing information, if available, also may prove important in determining whether treatments previously considered failures were prematurely abandoned prior to their producing maximal

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benefit. Physical examination should include general and spe-cific physical assessments, as well as neurologic and musculo-skeletal system reviews.31,35

Specific assessments are recommended to identify different conditions. For example, if FM is suspected, the physical exam-ination should include assessment of tender points as identified in the American College of Rheumatology criteria for the diagno-sis of this condition.36 For LBP, straight-leg raise testing is rec-ommended, as well as evaluation of knee strength and reflexes, great toe and foot dorsiflexion strength, foot plantarflexion, and ankle reflexes.37 For suspected OA, the clinician should look for signs of inflammation such as swelling, warmth, discoloration, and limited range of motion. For neuropathic pain syndromes, laboratory tests such as nerve conduction studies, somatosen-sory-evoked potentials, and quantitative sensory testing may be helpful, as may neurologic examination including evaluation for sensory abnormalities such as allodynia and hyperalgesia.27

Overall, the best indicator of pain is a patient’s self-report.30 Pain assessment tools and functional assessment tools may be useful in this regard (Table 1, page 18).30,38-49 These include unidimensional scales that rate a single pain aspect, such as the Visual Analog Scale, Numeric Rating Scale, and Verbal Rating Scale; as well as multidimensional tools that rate several aspects of pain, such as the Brief Pain Inventory and McGill Pain Questionnaire. Nonverbal scales, such as the Wong-Baker FACES Pain Rating Scale and Pain Thermometer, may be more useful for patients who are cognitively impaired or for whom English is not a native language. In addition, specific assessment scales have been developed for different pain syndromes, including the Western Ontario and McMaster Universi-ties Osteoarthritis Index, the Neuropathic Pain Scale, the Oswestry Low Back Pain Questionnaire,50 and the Fibromyalgia Impact Ques-tionnaire (FIQ).51 Recently, reflecting current interest in the condition, a revised FIQ has been described,52 as well as the self-administered Fibromyalgia Assessment Scale.53

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Considering the biopsychosocial context in which chronic pain occurs, comorbidities—particularly sleep disorders, depression, anxiety, substance abuse, personality disorders, and history of child-hood abuse—should be evaluated.30 These conditions are common in patients with chronic pain and can have significant effects on QoL and functioning, as well as choice of treatment. For example, a lack of restorative sleep can perpetuate pain syndromes, and the pres-ence of a comorbid depressive disorder may suggest treatment with

Table 1. Examples of Validated Pain Assessment Tools30,38-49

Assessment Tool Description

Unidimensional

Visual Analog Scale Uses a continuous scale to rate pain intensity38-40

Numeric Rating Scale Uses numerals (eg, 0-10) to rate pain intensity39,40

Verbal Rating Scale Uses words to rate pain intensity40,41

Wong-Baker FACES Pain Rating Scale

Uses expressive faces to rate pain intensity42

Pain Thermometer Uses 7 pain descriptors (ranging from no pain to the most intense pain imaginable) to rate pain intensity43

Multidimensional

Brief Pain Inventory Evaluates pain intensity, associated impair-ment, and pain relief44

McGill Pain Questionnaire Assesses pain in sensory, affective, and evaluative terms; contains an intensity scale and other items45

Neuropathic Pain Scale and Questionnaire

Assesses distinct pain qualities associated with neuropathic pain46,47

Leeds Assessment of Neuro-pathic Symptoms and Signs (LANSS)

Distinguishes symptoms derived from neuro-pathic pain vs nociceptive pain; involves a bedside evaluation of pain and sensory dys-function in descriptive terms48

Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)

Assesses symptoms (eg, pain, stiffness, physical function) associated with osteoarthritis49

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a pain medication indicated for depression as well as pain. Discus-sion of issues that affect patient attitudes toward the meaning of chronic pain management also is important.30 These include coping patterns, such as passive or avoidant behaviors that reduce engage-ment in self-management activities; spiritual matters, such as belief in divine healing intervention; and perspectives on disability, such as catastrophizing or fear of losing social and cultural identity due to an inability to function in the home or at work.

In all examinations, a determination of the specific under-lying chronic pain condition (eg, LBP, OA, FM, DPNP) should be sought, because it can guide the choice of diagnostic studies, such as laboratory screening and imaging studies,24 and the selection of appropriate therapy.30 In addition, the pain mecha-nism should be determined if possible, because it too can affect the choice of treatment.30 Finally, any correctable cause of pain, such as acute injury, should be evaluated by the appropriate spe-cialist and corrected.24,30

General Principles in the Management of Chronic PainTreatment goals should be established within the biopsy-

chosocial model14,30 and may include improvement of biological symptoms, such as pain and sleep54; psychological issues, such as depression or maladaptive beliefs about pain14; and social issues, such as those related to job or family function.14

Once goals are established, published guidelines can be useful in developing treatment plans—including both pharmacologic and nonpharmacologic modalities—and are available for many prevalent chronic pain conditions.55-59 Within these recommendations, how-ever, individualization of treatment is crucial, taking into account each patient’s pain characteristics, treatment characteristics, and personal factors.24 Table 2 (pages 20-24) summarizes the evidence identified in the most current guidelines for the treatment of chronic pain of several underlying etiologies.17,55,57,60-63

Text continues on page 25

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Table 2. Current Treatment Approaches To Selected Chronic Pain Conditions (continued)Guidelines Level of Evidence Strength of

RecommendationRecommendations

Chronic pain

AGS Panel on Pharmacological Management of Persistent Pain in Older Persons (2009)17

Higha Strong,b 1st line APAP

Higha Strongb Nonselective NSAIDs Selective COX-2 inhibitors

Higha Strongb Nonselective NSAIDs and/or selective COX-2 inhibitors + gastroprotective agents in pts with ↑ GI risk

Higha (NP)Moderate (FM)c

Strongb Adjuvant analgesics for NP, FM

Moderatec Strongb Corticosteroids reserved for pain-related inflammation

Lowd Strongb Opioids for moderate to severe pain

Moderate (localized NP)Lowd (non-NP)

Strongb (localized NP)Weake (non-NP)

Topical lidocaine

Moderatec Weake Topical NSAIDs for localized non-NP

Moderatec Weake Topical agents (ie, capsaicin, menthol)

Lowd Weake Glucosamine, chondroitin, cannabinoids, botulinum toxin, α2-adrenergic agonists, calcitonin, vitamin D, bisphosphonates, ketamine

FM

EULAR evidence-based recommendations for the management of fibromyalgia syndrome (2008)60,61

Ibf Ag Antidepressants (ie, amitriptyline, fluoxetine, dulox-etine, milnacipran, moclobemide, and pirlindole)

Ibf Ag Tramadol

Ibf Ag Tropisetron, pramipexole, and pregabalin

IVh Di Simple analgesics (eg, APAP and weak opioids); corticosteroids and strong opioids not recommended

LBP

Diagnosis and treatment of low back pain: a joint clinical practice guideline from ACP and APS (2007)55

Fairj 1st line APAP

Goodk N/A NSAIDs

Goodk N/A TCAs

Fairj N/A Benzodiazepines

Fairj N/A Gabapentin

Fairj N/A Opioids, tramadol

17,55,57,60-63

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Table continues on next page



Chronic pain

AGS Panel on Pharmacological Management of Persistent Pain in Older Persons (2009)17

Higha Strong,b 1st line APAP

Higha Strongb Nonselective NSAIDs Selective COX-2 inhibitors

Higha Strongb Nonselective NSAIDs and/or selective COX-2 inhibitors + gastroprotective agents in pts with ↑ GI risk

Higha (NP)Moderate (FM)c

Strongb Adjuvant analgesics for NP, FM

Moderatec Strongb Corticosteroids reserved for pain-related inflammation

Lowd Strongb Opioids for moderate to severe pain

Moderate (localized NP)Lowd (non-NP)

Strongb (localized NP)Weake (non-NP)

Topical lidocaine

Moderatec Weake Topical NSAIDs for localized non-NP

Moderatec Weake Topical agents (ie, capsaicin, menthol)

Lowd Weake Glucosamine, chondroitin, cannabinoids, botulinum toxin, α2-adrenergic agonists, calcitonin, vitamin D, bisphosphonates, ketamine

FM

EULAR evidence-based recommendations for the management of fibromyalgia syndrome (2008)60,61

Ibf Ag Antidepressants (ie, amitriptyline, fluoxetine, dulox-etine, milnacipran, moclobemide, and pirlindole)

Ibf Ag Tramadol

Ibf Ag Tropisetron, pramipexole, and pregabalin

IVh Di Simple analgesics (eg, APAP and weak opioids); corticosteroids and strong opioids not recommended

LBP

Diagnosis and treatment of low back pain: a joint clinical practice guideline from ACP and APS (2007)55

Fairj 1st line APAP

Goodk N/A NSAIDs

Goodk N/A TCAs

Fairj N/A Benzodiazepines

Fairj N/A Gabapentin

Fairj N/A Opioids, tramadol

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NP

IASP: Pharmacologic management of neuro-pathic pain: evidence-based recommendations (2007)62,63

N/A A,l 1st line TCAs (eg, nortriptyline, desipramine)SNRIs (eg, duloxetine, venlafaxine)α2δ-ligands (gabapentin, pregabalin)Topical lidocaine

N/A A,l 2nd line OpioidsTramadol

N/A B,m 3rd line Other antiepileptics (eg, carbamazepine, lamotrigine, oxcarbazepine, topiramate, valproic acid), capsaicin, NMDA antagonists, SSRIs, bupropion, mexiletine

OA

OARSI recommendations for the management of hip and knee OA, Part II: OARSI evidence-based, expert consensus guidelines (2008)57

Ia (knee)n

Ia (hip)n93% Nonselective NSAIDs

Nonselective NSAIDs + gastroprotective agents or selective COX-2 inhibitors as alternatives in pts with ↑ GI risk

Ia (knee)n

IV (hip)h92% APAP (≤4 g/d)

Ia (NSAIDs)n

Ia (capsaicin)n85% Topical NSAIDs, capsaicin as adjuvant or alternative to

oral analgesics/anti-inflammatory agents

Ia (weak opioids)n

IV (strong opioids)h 78% 82%

Weak opioids, opioid analgesics for refractory pain in hip or knee OA; stronger opioids should be used only for severe pain

Ia (knee)n

Ib (hip)f78% Intra-articular injections of corticosteroids for pain

refractory to oral analgesic/anti-inflammatory agents and in symptomatic knee OA with effusions or local inflammation

Ia (knee)n

Ia (hip)n64% Intra-articular hyaluronate (hip or knee OA)

Ia (glucosamine)n

Ia (chondroitin)n63% Glucosamine and/or chondroitin sulfate (knee OA)

ACP, American College of Physicians; AGS, American Geriatrics Society; APAP, acetaminophen; APS, American Pain Society; COX-2, cyclooxygenase-2; EULAR, European League Against Rheumatism; FM, fibromyalgia; GI, gastrointestinal; IASP, International Association for the Study of Pain; LBP, low back pain; N/A, not applicable; NMDA, N-methyl-d-aspartic acid; NP, neuropathic pain; NSAID, nonsteroidal anti-inflammatory drug;

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NP

IASP: Pharmacologic management of neuro-pathic pain: evidence-based recommendations (2007)62,63

N/A A,l 1st line TCAs (eg, nortriptyline, desipramine)SNRIs (eg, duloxetine, venlafaxine)α2δ-ligands (gabapentin, pregabalin)Topical lidocaine

N/A A,l 2nd line OpioidsTramadol

N/A B,m 3rd line Other antiepileptics (eg, carbamazepine, lamotrigine, oxcarbazepine, topiramate, valproic acid), capsaicin, NMDA antagonists, SSRIs, bupropion, mexiletine

OA

OARSI recommendations for the management of hip and knee OA, Part II: OARSI evidence-based, expert consensus guidelines (2008)57

Ia (knee)n

Ia (hip)n93% Nonselective NSAIDs

Nonselective NSAIDs + gastroprotective agents or selective COX-2 inhibitors as alternatives in pts with ↑ GI risk

Ia (knee)n

IV (hip)h92% APAP (≤4 g/d)

Ia (NSAIDs)n

Ia (capsaicin)n85% Topical NSAIDs, capsaicin as adjuvant or alternative to

oral analgesics/anti-inflammatory agents

Ia (weak opioids)n

IV (strong opioids)h 78% 82%

Weak opioids, opioid analgesics for refractory pain in hip or knee OA; stronger opioids should be used only for severe pain

Ia (knee)n

Ib (hip)f78% Intra-articular injections of corticosteroids for pain

refractory to oral analgesic/anti-inflammatory agents and in symptomatic knee OA with effusions or local inflammation

Ia (knee)n

Ia (hip)n64% Intra-articular hyaluronate (hip or knee OA)

Ia (glucosamine)n

Ia (chondroitin)n63% Glucosamine and/or chondroitin sulfate (knee OA)

OA, osteoarthritis; OARSI, Osteoarthritis Research Society International; pt, patient; RCT, randomized controlled trial; SNRI, serotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant

For table footnotes see next page

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Footnotes to Table 2a Evidence includes consistent results from well-designed, well-conducted studies in representative populations that directly assess effects on health outcomes (≥2 consistent, higher-quality RCTs or multiple, consistent observational studies with no significant methodological flaws showing large effects)�b Benefits clearly outweigh risks and burden OR risks and burden clearly outweigh benefits�c Evidence is sufficient to determine effects on health outcomes, but the strength of the evidence is limited by the number, quality, size, or consistency of included studies; generalizability to routine practice; or indirect nature of the evidence on health outcomes (≥1 higher-quality trial with greater than 100 subjects; ≥2 higher-quality trials with some inconsistency; ≥2 consistent, lower-quality trials; or multiple, consistent observational studies with no significant methodologic flaws showing at least moderate effects)�d Evidence is insufficient to assess effects on health outcomes because of limited number or power of studies, large and unexplained inconsistency between higher-quality studies, important flaws in study design or conduct, gaps in the chain of evidence, or lack of information on important health outcomes�e Benefits finely balanced with risks and burden�f RCT�g Directly based on category I evidence�h Expert committee reports or opinion or clinical experience of respected authorities, or both�i Directly based on category IV evidence or extrapolated recommendation from category I, II, or Ill evidence�j Evidence is sufficient to determine effects on health outcomes, but the strength of the evidence is limited by the number, quality, size, or consistency of included studies; generalizability to routine practice; or indirect nature of the evidence on health outcomes (≥1 higher-quality trial of sufficient sample size; ≥2 higher-quality trials with some inconsistency; ≥2 consistent, lower-quality trials, or multiple consistent observational studies with no significant methodologic flaws)�k Evidence includes consistent results from well-designed, well-conducted studies in representative populations that directly assess effects on health outcomes (≥2 consistent, higher-quality trials)�l Consistent level 1 studies�m Consistent level 2 or 3 studies or extrapolations from level 1 studies�n Meta-analysis of RCTs�

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Both the persistent and breakthrough components of chronic pain must be treated. Although a detailed discussion of treat-ment strategies available for the management of BTP is beyond the scope of this monograph, certain general approaches may be useful. For example, pretreatment before known activity may help prevent precipitated BTP, administration of an immediate-release or rapid-onset analgesic may be effective for idiopathic BTP, and either shortening the dosing cycle or increasing the daily dose may be attempted for end-of-dose failure.33,34

In many cases, chronic pain is a lifelong condition for patients who must adjust their expectations about physical abilities and incorporate treatment into their daily routines. A strong physi-cian–patient relationship is key to achieving agreement on diag-nostic and treatment plans; such agreement, in patients with back pain, was associated with higher patient satisfaction and better health status outcomes.64 Clear communication between phy-sician and patient is needed to make clear the biopsychosocial nature of pain and the potential need for therapeutic adjustments over time.14 It can encourage patient compliance with prescribed regimens and diligence in the long-term effort to improve and sus-tain functionality.65

Also important in chronic pain management are ongoing assess-ment and treatment monitoring. Evaluation of treatment efficacy, as evident in analgesia and functionality, and AEs is an important com-ponent in making decisions about the maintenance or adjustment of treatment.24,66 Documentation of degree of success achieved with various modalities as related to prespecified patient goals also may support continuity of care as patients move through the health care system. In particular, the potential risks associated with cer-tain treatments should be monitored and documented. For exam-ple, use of nonsteroidal anti-inflammatory drugs (NSAIDs) in older patients requires routine assessment for gastrointestinal (GI) and renal toxicity, hypertension, heart failure, and other drug–disease and drug–drug interactions.17 Similarly, if opioids are being used,

26

patients must be assessed for aberrant behaviors.66,67 (See Pharma-cologic Treatment for discussion of these and other issues related to the prescribing of specific analgesic agents.)

Nonpharmacologic TreatmentFor many patients, the use of nonpharmacologic treatment

modalities is an important personal preference. Although these techniques are included in many of the professional guidelines described in Table 2, they generally are not supported as first-line therapies or monotherapy for chronic pain conditions. They can, however, be helpful when used in conjunction with an effec-tive analgesic regimen.57,68-71

Modalities with evidence for efficacy in the management of chronic pain include the following:

Physical rehabilitation with functional goals• 30; Exercise,• 30 particularly for patients with OA57 and FM72;Mechanical interventions (eg, patellar taping, knee braces); •Massage therapy• 30; Education and cognitive-behavioral interventions• 30,73; Transcutaneous electrical nerve stimulation, particularly for •patients with LBP30; Complementary and alternative therapies (eg, acupunc-•ture)71; andSurgery (eg, total joint replacement, spinal fusion).• 24

Pharmacologic TreatmentAn array of analgesic agents is available. Table 3 (pages

28-37)lists detailed dosing, AEs, and other important informa-tion for medications that are included in published guidelines as first- or second-line treatments for the selected chronic pain conditions discussed in this monograph: LBP, OA, FM, and DPNP.17,30,55,57,60,62,74-109 Neither the table nor this monograph is intended to represent a complete overview of all pain types and agents. In addition, although headache represents a common

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chronic pain etiology, in keeping with current conventional clas-sifications, it is excluded here.

Among pharmacologic treatment options, oral administration generally is preferred because of its convenience, although other routes, such as topical, intravenous, intraspinal, trigger point injection, and nerve block injection, are available.24 Regardless of the route of administration, attention should be paid to the pain diagnosis, mechanism, functional effects, patient preference, and functional goals. Risk assessment also is a necessary component of determining an initial or adjusted treatment strategy in chronic pain, as certain classes of medication carry unique risks.

Nonopioid Analgesics

Published treatment guidelines have recommended acetamino-phen (APAP), which is analgesic and antipyretic,77 for mild to mod-erate OA.57 Randomized controlled trial (RCT) data, however, are mixed, with some studies supporting the use of APAP in OA of the knee110 and OA of the hip or knee111 and at least one study demon-strating a negative result for APAP in OA of the knee.112 Generally, APAP is well tolerated,113 but long-term use carries risks for signif-icant hepatic or renal AEs.30 NSAIDs, including nonselective and COX-2 selective inhibitors, are effective in the treatment of many pain disorders and have been used widely by patients with OA or RA.114 A systematic review found these agents superior to APAP in OA,115 but recent RCTs generally have not examined the role of common NSAIDs in chronic pain, OA, RA, or LBP. The risks recently linked with the use of these drugs may limit their use, particularly with regard to GI and cardiovascular events77 and renal effects.116 Specifically, celecoxib, ibuprofen, and naproxen are being studied for cardiovascular risks.114 Selective COX-2 inhibitors do not offer complete protection against GI bleeding,17,35 and other NSAID-related toxicities are similar in both COX-2 selective inhibitors and nonselective NSAIDs.17,35

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Table 3. Selected Pharmacologic Agents for Chronic Pain (continued)

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Nonopioids

Anticonvulsants

Gabapentin 17,62,74-78

300 mg on day 1; 600 mg on day 2 (divided bid); 900 mg on day 3 (divided tid)

1,200-2,400 (3,600)

PHN Simple antacids ↓ bioavailability

Binds to α2δ sub-unit of presynaptic voltage-dependent calcium channels; ↓ release of presyn-aptic transmitters

Recommended for NP62; dose adjustment required in pts with renal dysfunction; ↓ dose with low creatinine clearance

Ataxia, diplopia, edema, nystagmus, sedation, weight gain

Pregabalin 17,62,76-79

150 mg/d; may ↑ to 300 mg/d within 1 wk (divided bid or tid)

300 (450-600)

NP associated with DPNP and PHN; FM

Under-goes minimal CYP450-related metabolism


Scheduled agent; recom-mended for NP62; dose adjustment required in pts with renal dysfunction

Ataxia, somnolence, dry mouth, edema, diplopia, weight gain, difficulty with concentration or attention

Antidepressants—SNRIs

Duloxetine 17,62,76-78,80

30 mg qd 60 (60) MDD; GAD; NP associated with DPN; FM

Metabolized by CYP2D6; potent inhibitors of CYP1A2 should be avoided

Inhibits serotonin and norepinephrine reuptake

Recommended for NP62; contraindicated in pts with glaucoma or taking MAOIs

Anorexia, ataxia, con-stipation, dry mouth, hyperhidrosis, nausea, sedation

Milnacipran 17,77,81

12.5 mg on the first day; ↑ to 100 mg/d over 1 wk

100 (200)

FM Under-goes minimal CYP450-related metabolism


Discontinuation requires tapering; caution in renal insufficiency with creati-nine clearance <30 mL/min, reduce dose by 50%; contraindicated in pts with glaucoma or taking MAOIs

Nausea, headache, constipation, dizziness, insomnia, hot flush, hyperhidrosis, vomit-ing, palpitations, ↑ heart rate, dry mouth, hypertension

Venlafaxine 17,62,76-78,82

37.5 mg/d; ↑ weekly by 37.5 mg/d

150-225 (375)

MDD, GAD, social anxiety disorder, panic disorder

Metabolized by CYP2D6, CYP3A4


Recommended for NP62; dose adjustment required in pts with renal dysfunction; contraindicated in pts tak-ing MAOIs

Anorexia, anxiety, ataxia, constipation, dry mouth, hyperten-sion, insomnia, nausea, sedation

17,30,53,57,60,62,74-109

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Nonopioids

Anticonvulsants

Gabapentin 17,62,74-78

300 mg on day 1; 600 mg on day 2 (divided bid); 900 mg on day 3 (divided tid)

1,200-2,400 (3,600)

PHN Simple antacids ↓ bioavailability


Recommended for NP62; dose adjustment required in pts with renal dysfunction; ↓ dose with low creatinine clearance

Ataxia, diplopia, edema, nystagmus, sedation, weight gain

Pregabalin 17,62,76-79

150 mg/d; may ↑ to 300 mg/d within 1 wk (divided bid or tid)

300 (450-600)

NP associated with DPNP and PHN; FM

Under-goes minimal CYP450-related metabolism


Scheduled agent; recom-mended for NP62; dose adjustment required in pts with renal dysfunction

Ataxia, somnolence, dry mouth, edema, diplopia, weight gain, difficulty with concentration or attention

Antidepressants—SNRIs

Duloxetine 17,62,76-78,80

30 mg qd 60 (60) MDD; GAD; NP associated with DPN; FM

Metabolized by CYP2D6; potent inhibitors of CYP1A2 should be avoided


Recommended for NP62; contraindicated in pts with glaucoma or taking MAOIs

Anorexia, ataxia, con-stipation, dry mouth, hyperhidrosis, nausea, sedation

Milnacipran 17,77,81

12.5 mg on the first day; ↑ to 100 mg/d over 1 wk

100 (200)

FM Under-goes minimal CYP450-related metabolism


Discontinuation requires tapering; caution in renal insufficiency with creati-nine clearance <30 mL/min, reduce dose by 50%; contraindicated in pts with glaucoma or taking MAOIs

Nausea, headache, constipation, dizziness, insomnia, hot flush, hyperhidrosis, vomit-ing, palpitations, ↑ heart rate, dry mouth, hypertension

Venlafaxine 17,62,76-78,82

37.5 mg/d; ↑ weekly by 37.5 mg/d

150-225 (375)

MDD, GAD, social anxiety disorder, panic disorder

Metabolized by CYP2D6, CYP3A4


Recommended for NP62; dose adjustment required in pts with renal dysfunction; contraindicated in pts tak-ing MAOIs

Anorexia, anxiety, ataxia, constipation, dry mouth, hyperten-sion, insomnia, nausea, sedation

17,30,53,57,60,62,74-109


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Nonopioids (continued)

Antidepressants—SSRI

Fluoxetine83 20 mg/d 20-80 (80)

MDD, obses-sive-compulsive disorder, bulimia nervosa, panic disorder

Inhibits activ-ity of CYP2D6; caution advised with other sero-tonergic drugs

Inhibits serotonin reuptake

May be considered in FM60; contraindicated in pts tak-ing MAOIs, pimozide, or thioridazine

Nausea, headache, insomnia, sexual dys-function; ↑ risk for suicidality in children, adolescents, and young adults (aged 18-24 y)

Antidepressants—TCAs

(eg, ami-triptyline, desipramine, imipramine, nortriptyline)17,62,75,76,78,84-88

10-25 mg qhs or in divided doses q12h; ↑ weekly by 10-25 mg/d

50-150 (100-150)

Depression; imipramine hydrochloride also indicated for childhood enuresis

Metabolized by CYP2D6 (note: rapid vs slow metabolizers), potentiate other sedatives

Act via bal-anced monoamine reuptake inhibi-tion (amitriptyline, imipramine) and targeted norepi-nephrine reuptake inhibition (desipra-mine, nortriptyline)

Recommended for NP62; ↑ AEs with amitriptyline, imipramine; contraindicated in pts with glaucoma or taking MAOIs; relatively con-traindicated in elderly and pts with CV disease

Cardiac conduction block, confusion, con-stipation, dry mouth, orthostatic hypotension, sedation, urinary reten-tion, weight gain

APAP 500-1,000 mg q6h; 325 mg q4h

2,000-4,000 (4,000)

OTC for pain, fever

Drugs (eg, car-bamazepine) that ↑ action of liver enzymes that metabolize APAP100

Is analgesic and antipyretic, with-out a specific anti-inflammatory effect77

Reduce maximum dose (4 g/24 h) 50% to 75% in pts with hepatic insufficiency or history of alcohol abuse17

Hepatocellular and renal risks30 especially with long-term use

Benzodiazepinea

Diazepam89,90 2-10 mg 2-4 times daily

20-40 (40)

Anxiety disor-ders, skeletal muscle spasm, convulsive disorders

Cimetidine, ketoconazole, omeprazole, fluvoxamine, and fluoxetine may inhibit liver enzymes that metabolize diazepam141

Enhances the effects of GABA in the brain

Scheduled agent; may be considered for pts with LBP for time-limited course55,90; generally not recommended for elderly pts17; contrain-dicated in pts with acute narrow angle glaucoma

Drowsiness, fatigue, ataxia, risk for abuse and addiction

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Antidepressants—SSRI

Fluoxetine83 20 mg/d 20-80 (80)

MDD, obses-sive-compulsive disorder, bulimia nervosa, panic disorder

Inhibits activ-ity of CYP2D6; caution advised with other sero-tonergic drugs

Inhibits serotonin reuptake

May be considered in FM60; contraindicated in pts tak-ing MAOIs, pimozide, or thioridazine

Nausea, headache, insomnia, sexual dys-function; ↑ risk for suicidality in children, adolescents, and young adults (aged 18-24 y)

Antidepressants—TCAs

(eg, ami-triptyline, desipramine, imipramine, nortriptyline)17,62,75,76,78,84-88

10-25 mg qhs or in divided doses q12h; ↑ weekly by 10-25 mg/d

50-150 (100-150)

Depression; imipramine hydrochloride also indicated for childhood enuresis

Metabolized by CYP2D6 (note: rapid vs slow metabolizers), potentiate other sedatives

Act via bal-anced monoamine reuptake inhibi-tion (amitriptyline, imipramine) and targeted norepi-nephrine reuptake inhibition (desipra-mine, nortriptyline)

Recommended for NP62; ↑ AEs with amitriptyline, imipramine; contraindicated in pts with glaucoma or taking MAOIs; relatively con-traindicated in elderly and pts with CV disease

Cardiac conduction block, confusion, con-stipation, dry mouth, orthostatic hypotension, sedation, urinary reten-tion, weight gain

APAP 500-1,000 mg q6h; 325 mg q4h

2,000-4,000 (4,000)

OTC for pain, fever

Drugs (eg, car-bamazepine) that ↑ action of liver enzymes that metabolize APAP100

Is analgesic and antipyretic, with-out a specific anti-inflammatory effect77

Reduce maximum dose (4 g/24 h) 50% to 75% in pts with hepatic insufficiency or history of alcohol abuse17

Hepatocellular and renal risks30 especially with long-term use

Benzodiazepinea

Diazepam89,90 2-10 mg 2-4 times daily

20-40 (40)

Anxiety disor-ders, skeletal muscle spasm, convulsive disorders

Cimetidine, ketoconazole, omeprazole, fluvoxamine, and fluoxetine may inhibit liver enzymes that metabolize diazepam141

Enhances the effects of GABA in the brain

Scheduled agent; may be considered for pts with LBP for time-limited course55,90; generally not recommended for elderly pts17; contrain-dicated in pts with acute narrow angle glaucoma

Drowsiness, fatigue, ataxia, risk for abuse and addiction


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Chon droitin 57,91,92

200-400 mg 2-3 times daily or 800-1,200 mg once daily

800-1,200 (1,200)

OTC for OA Anticoagulant and antiplatelet drugs

Enhances the pro-tective metabolic response of chon-drocytes to stress

May be effective in knee OA Nausea, pain in mid-dle upper abdomen, diarrhea, constipation, lower extremity edema, hair loss, elevated blood pressure, heart palpitations

Cortico steroids

(eg, pred-nisone, prednisolone, methylpred-nisolone, dexame-thasone, triamcino-lone)93-95

Dosages vary; refer to individual PIs; route of administration may be oral or injectable (eg, intra-articular injection in knee or hip OA)57

Endocrine disor-ders, rheumatic disorders, col-lagen diseases, dermatologic diseases, aller-gic states, ophthalmic diseases, respi-ratory diseases, hematologic disorders, neoplastic diseases, edem-atous states, GI diseases, mul-tiple sclerosis, tuberculosis meningitis, trich-inosis

Drugs that induce hepatic enzymes (eg, phenobarbi-tal); drugs that inhibit metabolism of corticosteroids (eg, trolean-domycin); use caution with NSAIDs and oral anticoagulants

Influence cells involved in immune and inflammatory responses

Effective in many rheumatic and autoimmune condi-tions; AEs often limit use to low-dose, short-term admin-istration or to use in pts near end of life17

Fluid retention, mus-cle weakness, ↑ blood pressure, mood swings, weight gain, glaucoma, cataracts, infections, osteoporosis, men-strual irregularities, fragile skin, impaired wound healing, adrenal suppression

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Chon droitin 57,91,92

200-400 mg 2-3 times daily or 800-1,200 mg once daily

800-1,200 (1,200)

OTC for OA Anticoagulant and antiplatelet drugs


May be effective in knee OA Nausea, pain in mid-dle upper abdomen, diarrhea, constipation, lower extremity edema, hair loss, elevated blood pressure, heart palpitations

Cortico steroids

(eg, pred-nisone, prednisolone, methylpred-nisolone, dexame-thasone, triamcino-lone)93-95

Dosages vary; refer to individual PIs; route of administration may be oral or injectable (eg, intra-articular injection in knee or hip OA)57

Endocrine disor-ders, rheumatic disorders, col-lagen diseases, dermatologic diseases, aller-gic states, ophthalmic diseases, respi-ratory diseases, hematologic disorders, neoplastic diseases, edem-atous states, GI diseases, mul-tiple sclerosis, tuberculosis meningitis, trich-inosis

Drugs that induce hepatic enzymes (eg, phenobarbi-tal); drugs that inhibit metabolism of corticosteroids (eg, trolean-domycin); use caution with NSAIDs and oral anticoagulants

Influence cells involved in immune and inflammatory responses

Effective in many rheumatic and autoimmune condi-tions; AEs often limit use to low-dose, short-term admin-istration or to use in pts near end of life17

Fluid retention, mus-cle weakness, ↑ blood pressure, mood swings, weight gain, glaucoma, cataracts, infections, osteoporosis, men-strual irregularities, fragile skin, impaired wound healing, adrenal suppression


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Glucosa-mine57,96

500 mg 3 times daily or 1,500 mg once daily

1,500 (1,500)

OTC for OA Diabetes med-ications, drugs that ↑ risk for bleeding (eg, aspirin, anti-coagulants, antiplatelet drugs, NSAIDs)


May be effective in knee OA; caution advised in pts with shellfish allergy or iodine hypersensitivity, pts with diabetes or hypogly-cemia or taking agents that affect blood sugar, and pts with bleeding disorders or taking drugs that ↑ risk for bleeding

Upset stomach, drows-iness, insomnia, headache, skin reac-tions, sun sensitivity, nail toughening, tempo-rary ↑ blood pressure and heart rate, palpi-tations, high blood sugar in pts with diabe-tes or hyperglycemia, increased risk for bleeding

Hyaluronates (hyaluronans)57,97,98

(eg, sodium hyaluronate, high-molec-ular-weight hyaluronan, 1% sodium hyaluronate, hylan G-F 20)

IA administration; dosages vary; refer to individual PIs

Knee OA None known ↑ the visco elasticity of synovial fluid98

May be useful in pts with knee or hip OA

Arthralgia, arthrosis, back pain, injection site pain, limb pain, skin irritation97,101

NSAIDs

(eg, ibu-profen, naproxen, naproxen sodium, meloxicam, celecoxib, diclofenac sodium topi-cal gel 1%)

Dosages vary; refer to indi-vidual PIs

Refer to individ-ual PIs

Diuretics, lithium, meth-otrexate, warfarin-type anticoagulants, ACE inhibitors102

Inhibit activity of COX enzyme, thereby inhibit-ing prostaglandin synthesis102,103

Effective pain relief; pts with CV disease or risk factors for CV disease may be at greater risk for AEs; elderly patients are at greater risk for serious GI AEs104

CV and GI risks; for top-ical NSAIDs, application site reactions such as dermatitis

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Glucosa-mine57,96

500 mg 3 times daily or 1,500 mg once daily

1,500 (1,500)

OTC for OA Diabetes med-ications, drugs that ↑ risk for bleeding (eg, aspirin, anti-coagulants, antiplatelet drugs, NSAIDs)


May be effective in knee OA; caution advised in pts with shellfish allergy or iodine hypersensitivity, pts with diabetes or hypogly-cemia or taking agents that affect blood sugar, and pts with bleeding disorders or taking drugs that ↑ risk for bleeding

Upset stomach, drows-iness, insomnia, headache, skin reac-tions, sun sensitivity, nail toughening, tempo-rary ↑ blood pressure and heart rate, palpi-tations, high blood sugar in pts with diabe-tes or hyperglycemia, increased risk for bleeding

Hyaluronates (hyaluronans)57,97,98

(eg, sodium hyaluronate, high-molec-ular-weight hyaluronan, 1% sodium hyaluronate, hylan G-F 20)

IA administration; dosages vary; refer to individual PIs

Knee OA None known ↑ the visco elasticity of synovial fluid98

May be useful in pts with knee or hip OA

Arthralgia, arthrosis, back pain, injection site pain, limb pain, skin irritation97,101

NSAIDs

(eg, ibu-profen, naproxen, naproxen sodium, meloxicam, celecoxib, diclofenac sodium topi-cal gel 1%)

Dosages vary; refer to indi-vidual PIs

Refer to individ-ual PIs

Diuretics, lithium, meth-otrexate, warfarin-type anticoagulants, ACE inhibitors102

Inhibit activity of COX enzyme, thereby inhibit-ing prostaglandin synthesis102,103

Effective pain relief; pts with CV disease or risk factors for CV disease may be at greater risk for AEs; elderly patients are at greater risk for serious GI AEs104

CV and GI risks; for top-ical NSAIDs, application site reactions such as dermatitis


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Topical agents

Capsaicin 0.025% cream 4 times daily57

0.025%-0.25% cream (0.25% cream)105

OTC for pain None known107 Acts via agonist activity at the tran-sient receptor potential vanilloid receptor 1108

Can be effective in knee OA and other regional pain syndromes17,57

Burning, stinging, ery-thema at application site; coughing106

Lidocaine patch 5%99

≤3 patches (each 700 mg) once for ≤12 h within a 24-h period

700-2,100 (2,100)62

Pain associated with PHN

Class I antiar-rhythmic drugs (eg, tocain-ide, mexiletine); other local anesthetic agents

Stabilizes neu-ronal membranes by inhibiting the ionic fluxes required for the initiation and conduction of impulses

Recommended for localized peripheral NP and local-ized nonneuropathic pain; not recommended for cen-tral NP62,17

Application site reac-tions such as blisters, bruising, and burning sensation; systemic AEs, although unlikely, may include CNS exci-tation or depression

Opioids

(eg, mor-phine, morphine sulfate, methadone, oxycodone, oxymor-phone, fentanyl, tramadol, levorphanol, hydromor-phone, tapentadol)

Dosages vary; refer to individual PIs

Various; refer to individual PIs; generally, mod-erate to severe pain

A number of hepatic drug interactions may influence opioid drug levels109

Act at various opi-oid receptors within the peripheral and central nervous systems109

Scheduled agents (except tramadol); for pts with refractory hip or knee OA where other agents are inef-fective or contraindicated57; can be considered for pts with NP, LBP, or other chronic pain17,55,62; weigh risks for abuse and addiction

Constipation, nausea, somnolence, respiratory depression, endocri-nologic abnormalities; risk for abuse and addiction17,77

ACE, angiotensin-converting enzyme; AE, adverse event; APAP, acetaminophen; CNS, central nervous system; COX, cyclooxygenase; CV, cardiovascular; DPNP, diabetic peripheral neuropathic pain; FM, fibromyalgia; GABA, γ-amino-butyric acid; GAD, generalized anxiety disorder; GI, gastrointestinal; IA, intra-articular; MAOI, monoamine oxidase inhibitor; MDD, major depressive disorder; NP, neuropathic pain; NSAID, nonsteroidal anti-inflammatory drug;

37


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Sche

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ffec

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ose

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AEs


Topical agents

Capsaicin 0.025% cream 4 times daily57

0.025%-0.25% cream (0.25% cream)105

OTC for pain None known107 Acts via agonist activity at the tran-sient receptor potential vanilloid receptor 1108

Can be effective in knee OA and other regional pain syndromes17,57

Burning, stinging, ery-thema at application site; coughing106

Lidocaine patch 5%99

≤3 patches (each 700 mg) once for ≤12 h within a 24-h period

700-2,100 (2,100)62

Pain associated with PHN

Class I antiar-rhythmic drugs (eg, tocain-ide, mexiletine); other local anesthetic agents

Stabilizes neu-ronal membranes by inhibiting the ionic fluxes required for the initiation and conduction of impulses

Recommended for localized peripheral NP and local-ized nonneuropathic pain; not recommended for cen-tral NP62,17

Application site reac-tions such as blisters, bruising, and burning sensation; systemic AEs, although unlikely, may include CNS exci-tation or depression

Opioids

(eg, mor-phine, morphine sulfate, methadone, oxycodone, oxymor-phone, fentanyl, tramadol, levorphanol, hydromor-phone, tapentadol)

Dosages vary; refer to individual PIs

Various; refer to individual PIs; generally, mod-erate to severe pain

A number of hepatic drug interactions may influence opioid drug levels109

Act at various opi-oid receptors within the peripheral and central nervous systems109

Scheduled agents (except tramadol); for pts with refractory hip or knee OA where other agents are inef-fective or contraindicated57; can be considered for pts with NP, LBP, or other chronic pain17,55,62; weigh risks for abuse and addiction

Constipation, nausea, somnolence, respiratory depression, endocri-nologic abnormalities; risk for abuse and addiction17,77

OA, osteoarthritis; OTC, over-the-counter; PHN, postherpetic neuralgia; PI, prescribing information; pt, patient; SNRI, serotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressanta Benzodiazepines are intended for short-term use only due to risks for abuse, misuse, and physical dependency�

38

A range of antidepressant medications exhibits analge-sic properties,77 although they vary in ratings of efficacy and safety. Tricyclic antidepressants, for example, are effective in pain management but have a substantial AE profile, including cardiovascular AEs and falls in older patients.77 Selective sero-tonin reuptake inhibitors have been studied but are relatively ineffective in the treatment of chronic pain.77,117 Serotonin norepinephrine reuptake inhibitors (SNRIs), on the other hand, have demonstrated benefit in the management of chronic pain conditions, including LBP, OA, and DPNP. 117-120 Three SNRIs with evidence for use in chronic pain conditions currently are available in the United States: duloxetine, milnacipran, and venlafaxine (although milnacipran is FDA-approved for fibro-myalgia, not depression). Of these, duloxetine has the most indications for chronic pain (FM, DPNP),121-124 and this agent has shown efficacy in RCTs in OA and LBP.125,126 Venlafaxine is not FDA-approved for any pain indication. AEs associated with SNRIs include nausea and insomnia; duloxetine and milnacip-ran are better tolerated than venlafaxine.117

Certain anticonvulsants also are used for their analgesic properties in the management of chronic pain. Gabapentin and pregabalin, in particular, are useful for neuropathic pain con-ditions.77,127 Pregabalin is FDA-approved for FM, DPNP, and postherpetic neuralgia (PHN); carbamazepine is approved for trigeminal neuralgia; and gabapentin is approved for PHN. In addition, RCTs have demonstrated a role for gabapentin in the treatment of traumatic nerve injury pain128 and other types of neuropathic pain.129 Although not approved for a pain indica-tion, lamotrigine has shown evidence in RCTs of efficacy in treating DPNP and HIV-associated sensory neuropathies and is recommended in guidelines as a second-tier agent for DPNP. AEs for this class of agents include somnolence, diz-ziness, and nausea but do vary depending on the individual medication.130-132

39

Skeletal muscle relaxants may be helpful for certain pain con-ditions. Cyclobenzaprine has a structure nearly identical to that of the tricyclic antidepressant amitriptyline, and according to FM treatment guidelines developed by the American Pain Society, it may be effective for some patients being treated for this disor-der.77 Other medications that often are classified broadly as skele-tal muscle relaxants (baclofen, dantrolene, tizanidine, carisoprodol, chlorzoxazone, metaxalone, methocarbamol, orphenadrine) are believed to have a limited role in treating chronic pain.77

Topical analgesics have the advantage of a lower risk for the development of systemic side effects compared with oral anal-gesics77 and were preferred to oral ibuprofen among patients with knee pain in 2 studies.133 Topical analgesics commercially available for chronic pain include the NSAID diclofenac, as well as lidocaine and capsaicin.57,77,134,135 These agents have the dis-advantages of being able to treat only a localized area of pain and of irritating skin reactions in a minority of patients.77

Opioid Analgesics

Opioids have long been used for acute and chronic can-cer pain,136 and many clinicians and investigators believe that these agents can be effective in chronic noncancer pain as well, in carefully selected and monitored patients.136 However, opi-oids are associated with AEs, such as nausea and constipa-tion, peripheral edema, and endocrine abnormalities, and may be misused and frankly abused. When patients are being con-sidered for opioid treatment, their risk for opioid abuse must be assessed and managed appropriately.67 Risk stratification and ongoing monitoring are needed for the person being treated with opioids.67,77,136 Importantly, the FDA has announced that it will require the manufacturers of certain opioid products to cre-ate and implement a Risk Evaluation and Mitigation Strategy,137 which may include restricted distribution through trained pre-scribers and pharmacies.138

40

Multidrug Therapy

In some cases, multidrug therapy can be considered. This strategy attempts to maximize analgesic efficacy and reduce AEs by incorporating agents with differing mechanisms of action that target several points along pain pathways at lower doses than in monotherapy.139 A seminal study illustrating this approach compared monotherapy using morphine or gabapen-tin alone with coadministration of the 2 agents for patients with neuropathic pain.140 Subjects who received combination ther-apy experienced greater pain relief at lower doses of each agent than did those who received either agent alone. AEs were sim-ilar in all treatment groups, except that the combination ther-apy resulted in higher frequency of constipation than gabapentin alone and higher frequency of dry mouth than morphine alone.

Multidrug therapy raises several unresolved issues and should be used with caution, especially among older patients, in whom age-related effects on pharmacokinetic and pharma-codynamic characteristics may enhance the rates and sever-ity of drug interactions.17,141 In the general population, as well, selection of agents for multidrug therapy should be carefully undertaken, with due consideration for such issues as drug inter-actions and mechanisms of action.142

ConclusionChronic pain is common and frequently disabling. It can

develop in a number of conditions, including LBP, OA, FM, and DPNP. Regardless of underlying etiology, chronic pain requires comprehensive initial and ongoing assessment as well as appro-priate pharmacologic and nonpharmacologic treatment guided by biopsychosocial considerations, relevant published guide-lines, and individual patient characteristics.

41

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Chappell AS, Ossanna MJ, Liu-Seifert H, et al. Duloxetine, a centrally acting analgesic, in 125. the treatment of patients with osteoarthritis knee pain: A 13-week, randomized, placebo-controlled trial. Pain. 2009 Jul 20 [Epub ahead of print].

Skljarevski V. Efficacy and safety of duloxetine 60 mg to 120 mg once daily in patients with 126. CLBP. Presented at American Academy of Pain Medicine 2009 Annual Meeting; January 29, 2009; Honolulu, HI. Abstract 206.

Sabatowski R, Galvez R, Cherry DA, et al. Pregabalin reduces pain and improves sleep 127. and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Pain. 2004;109(1-2):26-35.

Gordh TE, Stubhaug A, Jensen TS, et al. Gabapentin in traumatic nerve injury pain: 128. a randomized, double-blind, placebo-controlled, cross-over, multi-center study. Pain. 2008;138(2):255-266.

Serpell MG. Gabapentin in neuropathic pain syndromes: a randomised, double-blind, 129. placebo-controlled trial. Pain. 2002;99(3):557-566.

Maizels M, McCarberg B. Antidepressants and antiepileptic drugs for chronic non-cancer 130. pain. Am Fam Physician. 2005;71(3):483-490.

Eisenberg E, Lurie Y, Braker C, Daoud D, Ishay A. Lamotrigine reduces painful diabetic 131. neuropathy: a randomized, controlled study. Neurology. 2001;57(3):505-509.

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CME Post-TestDirections: choose the single-letter response that best answers the question or completes the sentence and record your answers in the Post-Test Answer Key on page 53.

Chronic pain ________.1. a. does not include cognitive or emotional componentsb. is maladaptivec. is limited to an expected healing timed. serves a useful function

The consequences of chronic pain do not include ________.2. a. lower quality of lifeb. greater fatiguec. higher productivityd. low self-rated health

Which of the following has been hypothesized as a 3. mechanism of pain?a. Peripheral sensitizationb. Central sensitizationc. Augmented facilitationd. All of the above

Which of the following is not a unidimensional scale for 4. assessing pain?a. Brief Pain Inventoryb. Visual Analog Scalec. Numeric Rating Scaled. Verbal Rating Scale

Which of the following is most useful in establishing 5. treatment goals?a. Non-individualization of treatmentb. Biopsychosocial modelc. Restricting therapy to either nonpharmacologic or

pharmacologic modalitiesd. All of the above

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Nonpharmacologic treatment modalities for chronic pain do 6. not include ________.a. exerciseb. massage therapyc. topical analgesicsd. physical rehabilitation with functional goals

Nonsteroidal anti-inflammatory drugs ________.7. a. do not have gastrointestinal or cardiovascular risksb. are not often used by patients with osteoarthritisc. include tricyclic antidepressantsd. are effective in the treatment of many pain disorders

Which is not a serotonin norepinephrine reuptake inhibitor?8. a. duloxetineb. gabapentinc. milnaciprand. venlafaxine

Pregabalin is not FDA-approved for __________.9. a. fibromyalgiab. diabetic peripheral neuropathic painc. osteoarthritisd. postherpetic neuralgia

Adverse events commonly associated with opioids do not 10. include ________.a. diplopiab. nauseac. constipationd. endocrine abnormalities

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Evaluation Form

Chronic Pain in Perspective: Recent Evidence and Clinical ImplicationsPostgraduate Institute for Medicine is committed to excellence in con-tinuing education, and your opinions are critical in this effort. To assist in evaluating the effectiveness of this activity and to make recommen-dations for future educational offerings, please take a few minutes to complete this evaluation form. You must complete this evaluation form to receive acknowledgment for completing this activity.

Please rate your level of agreement by circling the appropriate ratings:1 = Strongly disagree 2 = Disagree 3 = Neutral 4 = Agree 5 = Strongly agree

Educational Objectives

After participating in this activity, I am now better able to:

Describe pathophysiologic mechanisms that have been proposed for 1. prevalent chronic pain conditions (low back pain, osteoarthritis, fibro-myalgia, and diabetic peripheral neuropathic pain). 1 2 3 4 5

Restate the rationale for initial and ongoing evaluation of chronic pain 2. and restoration of function. 1 2 3 4 5

Summarize available primary and consensus evidence on optimal 3. nonpharmacologic and pharmacologic treatment strategies for management of prevalent chronic pain conditions. 1 2 3 4 5

Discuss evidence-based strategies for the use of first-, second-, and 4. third-line pharmacotherapy options for chronic pain. 1 2 3 4 5

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Based on your participation in this activity, choose the statement(s) that apply:❏ I gained new strategies/skills/information that I can apply to my area

of practice.❏ I plan to implement new strategies/skills/information into my

practice.

What strategies/skills/information do you plan to implement into your practice?________________________________________________________________________________________________________

What barriers do you see to making a change in your practice?________________________________________________________________________________________________________

Which of the following best describes the impact of this activity on your performance?❏ I will implement the information in my area of practice.❏ I need more information before I can change my practice behavior.❏ This activity will not change my practice, as my current practice is

consistent with the information presented.❏ This activity will not change my practice, as I do not agree with the

information presented.

Please rate your level of agreement by circling the appropriate ratings:1 = Strongly disagree 2 = Disagree 3 = Neutral 4 = Agree 5 = Strongly agreeThe content presented:Enhanced my current knowledge base 1 2 3 4 5Addressed my most pressing questions 1 2 3 4 5Promoted improvements or quality in health care 1 2 3 4 5Was scientifically rigorous and evidence-based 1 2 3 4 5Avoided commercial bias or influence 1 2 3 4 5

Are you willing to participate in a post-activity follow-up survey? ❏ Yes ❏ No

Please list any topics you would like to see addressed in future educa-tional activities:________________________________________________________________________________________________________

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To receive acknowledgment for completing this activity, please complete the post-test answer key by recording the best answer to each question, complete this evaluation form, and send it to Postgraduate Institute for Medicine via fax, to (303) 790-4876 or mail, to 367 Inverness Parkway, Suite 215, Englewood, CO 80112.

Online participation is available at www.cmeuniversity.com (click on “Find Post-Test/Evaluation by Course” in the navigation menu, and search by Project ID 6759) and www.CMEZone.com (enter project code PG0923 in the keyword field).

Post-Test Answer Key

1 2 3 4 5 6 7 8 9 10

Request for Credit

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Date: ________________________________________________

For Physicians OnlyI certify my actual time spent to complete this educational activity to be: ____❏ I participated in the entire activity and claim 1.0 credit.❏ I participated in only part of the activity and claim _____ credit(s).

Project ID: 6759PG0923

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Notes

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Notes

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Documents

Chronic Pain · Director, Comprehensive Pain Program Albany Medical Center Albany, New York Bill H. McCarberg, MD Founder Chronic Pain Management Program Kaiser Permanente Escondido,