A Guide to Advances inpain Management

Transcription

1 A Guide to Advances inpain Management A Synopsis of Roundtable Discussions Orlando, Florida 2008 Target audience: pain physicians This program is jointly sponsored by the Supported by an educational grant from and PharmaCom Group, Inc.

2 Faculty Charles E. Argoff, MD Albany Medical College Albany Medical Center, Comprehensive Pain Program Albany, New York Rollin M. Gallagher, MD, MPH Penn Pain Medicine, University of Pennsylvania Philadelphia Veterans Affairs Medical Center Philadelphia, Pennsylvania Douglas L. Gourlay, MD Wasser Pain Management Centre, Mount Sinai Hospital Addiction Medicine Clinic, Centre for Addiction and Mental Health Toronto, Ontario, Canada Howard A. Heit, MD Georgetown University School of Medicine Washington, DC Michael H. Moskowitz, MD, MPH University of California Davis School of Medicine Sacramento, California Bay Area Pain Medical Associates Mill Valley, California Steven D. Passik, PhD Memorial Sloan-Kettering Cancer Center New York, New York Steven P. Stanos Jr, DO Rehabilitation Institute of Chicago, Center for Pain Management Northwestern University Medical School Chicago, Illinois Lynn R. Webster, MD Lifetree Clinical Research and Pain Clinic Salt Lake City, Utah Accreditation The University of Nebraska Medical Center, Center for Continuing Education (UNMC CCE) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The UNMC CCE designates this educational activity for a maximum of 2 AMA PRA Category 1 Credits TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and Policies of the ACCME through the joint sponsorship of the UNMC CCE and PharmaCom Group, Inc. Continuing Education Credit To receive CME credit, you must complete the evaluation, post-test, and registration online at The evaluation provides each participant with the opportunity to comment on the quality of the instructional process, the perception of enhanced professional effectiveness, the perception of commercial bias, and his or her views on future educational needs. A statement of credit will be available for printing online upon completion of the evaluation. Start date is April 15, No credit will be given after April 15, Please direct any CME-related questions to UNMC CCE at or dfrost@unmc.edu Learning Objectives After completion of this activity, participants will be better able to: Identify chronic pain patients who have comorbid psychiatric disorders Formulate strategies to prevent/lessen abuse and/or diversion when managing pain Summarize the clinical trial evidence and clinical experience of topically applied analgesics

3 Faculty Disclosures In accordance with the ACCME, the UNMC CCE requires that any person who is in a position to control the content of a CME activity must disclose all relevant financial relationships held with a commercial interest. Accordingly: the UNMC CCE staff and PharmaCom Group, Inc, staff who were involved in the development of this activity have no financial relationships with any commercial interests that are relevant to this activity. See each section for individual faculty disclosures. Disclaimer The content and views presented in this educational activity are those of the faculty and do not necessarily reflect those of the UNMC CCE or PharmaCom Group, Inc. This material is prepared based upon a review of multiple sources of information, but it is not exhaustive of the subject matter. Therefore, health care professionals and other individuals should review and consider other publications and materials on the subject matter before relying solely upon the information contained in this educational activity. The reader is also urged to consult the full prescribing information on any drug mentioned in this publication for recommended dosages, indications, contraindications, warnings, precautions, and adverse effects before prescribing any medication. This is particularly important when a drug is new or infrequently prescribed. Contents Multidimensional Issues in Pain Management Chronic Pain & Comorbid Psychiatric Disorders The Neurobiologic & Pharmacologic Interface of Pain & Psychiatric Disorders Technologies & Practices to Manage Risk Emerging Pharmaceutical Strategies to Reduce Opioid Abuse in Pain Management Clinical Utility of New Opioid Formulations With Potential to Deter Abuse Urine Drug Testing in Pain Medicine: Pearls & Pitfalls Nonsystemic Pharmacologic Treatments for Pain Topical Application of Analgesics Topical Agents for the Treatment of Chronic Pain Off-Label Usage Disclosure This activity contains information about commercial products/devices that are unlabeled for use or investigational uses of products not yet approved.

4 Multidimensional Issues in Pain Management Chronic Pain & Comorbid Psychiatric Disorders The Neurobiologic & Pharmacologic Interface of Pain & Psychiatric Disorders Disclosures: Rollin M. Gallagher, MD, MPH, reports that he has no financial relationships with any commercial entities that produce health care related products and/or services. Michael H. Moskowitz, MD, MPH, reports that he has no financial relationships with any commercial entities that produce health care related products and/or services. 2

5 Chronic Pain & Comorbid Psychiatric Disorders Chronic pain has an emotional component and is frequently accompanied by depression or anxiety. 1-4 Comorbid substance abuse is also commonly associated with chronic pain creating a dilemma for physicians when considering treatment with opioids, which have a well established abuse potential. 1,3,5 Therefore, in order to optimize outcomes, chronic pain management should be multidimensional, addressing both pain and psychiatric comorbidity. 1,3,6 The following report highlights the major points raised during a roundtable discussion led by Rollin M. Gallagher, MD, MPH, Clinical Professor of Psychiatry and Anesthesiology, Director for Pain Policy Research and Primary Care, Penn Pain Medicine, University of Pennsylvania, and Director of Pain Medicine, Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania. In particular, the biologic and psychosocial factors that may influence the course and outcome of chronic pain disorders were discussed, as well as ways in which to incorporate opioids into a treatment plan that maximizes the success of pain control while minimizing the risk of misuse, abuse, or addiction. 3,7 Why Identify Comorbid Psychiatric Disorders? Chronic pain can activate or worsen a preexisting psychosocial problem or psychiatric disorder. 3 Considering depression as an example, there is no unequivocal answer for whether depression precedes or follows the development of chronic pain, although more evidence supports the consequence hypothesis (depression following chronic pain) than the antecedent hypothesis (depression preceding pain). 1,8 Figure 1 depicts a hypothetical model for risk of depression for persons who experience chronic pain. 1,9 The stress of living with chronic pain causes some psychosocial problems for most patients, and clinically significant psychiatric disorders in many. 1,3,9 There is also some evidence for the scar hypothesis individuals with a personal or family history of depression may develop depression sooner after pain onset than will those without such histories. 1,8 When present, depression plays an important role in the experience of chronic pain patients with depression report higher pain levels, tend to be less active, report greater disability and greater interference due to pain, and display more pain behaviors. 1,6,10-12 There is a relationship between the severity of depression and the perception of pain intensity, with increasing symptoms of depression associated with greater pain-related impairment. 1,8,13,14 Figure 1. Hypothetical risk model for depressive illness in persons who develop chronic pain 1 Risk of depression after pain 10 % Base rate in population Symptoms of anxiety may be prominent in patients with chronic pain for several reasons. 1 Patients with pain conditions commonly experience anxiety because of the stress of living with pain. 1 For example, the real and imagined consequences of disability can further complicate a pain disorder with comorbid generalized anxiety, while the stress of severe trauma may lead to posttraumatic stress disorder. 1 Although the prevalence of addiction among the chronic pain population is not necessarily greater than what would be expected from general population data, unrecognized substance abuse disorders can be worsened by pain treatment. 15 Confounding the problem, untreated depressive and anxiety disorders are associated with even higher rates of substance use problems among chronic pain patients treated with opioids. 16 The nonpsychiatric physician treating chronic pain must assess and address emotions, behavior, and psychiatric comorbidity, because when ignored, concomitant problems render the chronic pain treatment by even the most skillful physician ineffective. 3 Therefore, all patients with chronic pain disorders should be screened for psychiatric disorders. Screening Hypothetical ceiling rate for those with pre-pain risk Pain onset 6 months Time Hypothetical ceiling rate for those without pre-pain risk Past and family history of depression Past history of depression Family history of depression No past or family history of depression?40 % A number of diagnostic instruments are available to assess depression, anxiety, and substance abuse. However, embedding simple screening questions to assess psychiatric 3

6 Multidimensional Issues in Pain Management issues (eg, sleep disturbance, difficulty concentrating, depressed mood, poor energy, sexual functioning, anxiety, coping, and substance abuse) within the routine review of systems can be just as sensitive and less stigmatizing to the patient. 1,3,17 In addition, routinely asking such questions elevates these symptoms to clinical importance, so that patients may be more likely to report them if they should later emerge. 3 If screening is positive, a more thorough evaluation is needed to establish a definitive diagnosis, and to evaluate the presence of other comorbid psychiatric or medical conditions. 1 Suicide is the most common mortal complication of chronic pain, so a careful assessment of a patient s suicide risk should include the presence of suicidal ideation, intent, plans, and the availability and lethality of methods being contemplated. 1,3 Even when not detected initially, physicians should periodically screen for psychiatric problems during chronic pain treatment, particularly when symptoms, impairment, or disability change. 1 Managing Comorbidities Fortunately, treatment for common comorbidities such as depression and anxiety is usually very effective, although substance abuse and addiction are more difficult to manage. 3 Psychopharmacologic treatments of psychiatric comorbidities associated with chronic pain should be considered in a behavioral context. 1,3 Even if the pain physician chooses to refer treatment of a comorbid psychiatric disorder to others, he or she still has an important role in treatment. 3 Referral should be to a known colleague who will share information appropriately. 3,17 It is a critical part of an effective pain practice to develop community networks for the kinds of services that are commonly needed in a chronic pain population, such as treatment for depression, anxiety, substance abuse comorbidities. 1 Physicians should assure patients that such referrals are common in and critical to successful pain treatment. 1 The recommended pharmacotherapy of anxiety depends on the particular anxiety disorder. 1,3 However, there are a plethora of medications for depression, and no single antidepressant has proved more effective than any other. 1,3 More than 80% of depressed patients have a response to at least one medication, although individual antidepressants are effective in only 50% to 60% of patients. 1,3 Factors that are considered in selecting a particular antidepressant include a previous response to that medication, a family history of a response to that medication, and anticipated side effects. 1 Remission a complete recovery to normal should be the goal, rather than partial response with residual symptoms. 3 Antidepressants may ameliorate pain either by treating the masked depression in which pain is thought to be a symptom of the depression, or by treating manifest depression caused by the pain, which enables the patient to better tolerate the pain. 1 While antidepressants are equally efficacious in treating depression, some also have analgesic properties that can be utilized when managing patients with comorbid pain and depression. 1 For example, some antidepressants are thought to have direct analgesic effects by modulating pain perception through activity on noradrenergic and serotonergic neurophysiologic systems that descend from the midbrain to the dorsal horn. 1 Antidepressants with dual norepinephrine and serotonin reuptake inhibition activity, such as venlafaxine and duloxetine, provide superior pain relief compared with antidepressants that selectively act on either neurotransmitter alone. 1,3,18 In theory, these medications have the potential to relieve symptoms of neuropathic pain and depression at the same time through their dual action. 1,3,18 Inhibition of sodium channel activity in the neuronal membrane may also contribute to the analgesic properties of tricyclic antidepressants in neuropathic pain. 1 Structured Management When Prescribing Opioids There are considerable risks for physicians who prescribe opioids without first assessing patients for substance abuse or addiction history or potential, and without adequate monitoring of patients once therapy is initiated. 7 Such actions result in potentially mistreating chronic pain as well as missing the opportunity to identify and treat a comorbid substance use disorder. 7 Physicians who prescribe opioids for chronic pain should follow standard practice guidelines regarding assessment and monitoring to minimize risk of a negative outcome. 7,19,20,21 Patients at risk of substance abuse because of a personal or family history, or who display aberrant drug-taking behaviors, require more structured prescribing and monitoring, such as frequent visits, prescribing of small quantities of opioids, more frequent urine drug testing (UDT), pill counts, and education and counseling. 7 Universal Precautions It is not possible to determine beforehand, with any degree of certainty, who will become a problematic user of prescription opioids, and patient self-report of drug use 4

7 is frequently unreliable. 22 This awareness supports the universal precautions approach for all patients being considered for opioid therapy in order to estimate risk. 22 The universal application of chronic opioid policy, such as use of an opioid treatment agreement (OTA) and UDT conducted in a respectful and matter-of-fact manner, avoids selecting a patient on the basis of unreliable demographics. 7,22 Although efficacy of tools such as the OTA and UDT remains unproven, when used routinely for all patients, these tools can reduce stigma and minimize conflicts associated with opioid therapy. 7 Conclusion Depression, anxiety disorders, and substance abuse constitute the most common psychiatric comorbid conditions in patients with chronic pain disorders. 1,3 Treating pain without managing comorbidities, when present, will usually be ineffective. 1 Optimal outcomes for chronic pain require multidimensional treatment physicians should selectively and skillfully integrate treatment and coordinate any needed resources. 1,3 References 1. Gallagher RM, Verma S. Mood and anxiety disorders in chronic pain. In: Dworkin RH, Breitbart WS, eds. Psychosocial Aspects of Pain: A Handbook for Health Care Providers (Progress in Pain Research and Management, V. 27). Seattle, WA: IASP Press; 2004: Verma S, Gallagher RM. The psychopharmacologic treatment of depression and anxiety in the context of chronic pain. Curr Pain Headache Rep. 2002;6: Gallagher RM, Verma S. Biopsychosocial pain medicine: integrating psychiatric and behavioral therapies into medical treatment. Semin Neurosurgery. 2004;15: Kroenke K, Price RK. Symptoms in the community. Prevalence, classification, and psychiatric comorbidity. Arch Intern Med. 1993;153: Gourlay DL, Heit HA. Pain and addiction: managing risk through comprehensive care. J Addict Dis. 2008;27: Mossey J, Gallagher RM. Longitudinal experience of a nationally representative sample of the U.S. population 18 years and older: the importance of co-morbid major depression, alcohol and drug abuse. Pain Med. 2009;10: Abstract # Wiedemer NL, et al. The opioid renewal clinic: a primary care, managed approach to opioid therapy in chronic pain patients at risk for substance abuse. Pain Med. 2007;8: Fishbain DA, et al. Chronic pain-associated depression: antecedent or consequence of chronic pain? A review. Clin J Pain. 1997;13: Dohrenwend BP, et al. Why is depression comorbid with chronic myofascial face pain? A family study test of alternative hypotheses. Pain. 1999;83: Keefe FJ, et al. Depression, pain, and pain behavior. J Consult Clin Psychol. 1986;54: Haythornthwaite JA, et al. Depression and the chronic pain experience. Pain. 1991;46: Krause SJ, et al. Depression and pain behavior in patients with chronic pain. Clin J Pain. 1994;10: Mossey JM, et al. The effects of pain and depression on physical functioning in elderly residents of a continuing care retirement community. Pain Med. 2000;1: Mossey JM, Gallagher RM. The longitudinal occurrence and impact of comorbid chronic pain and chronic depression over two years in continuing care retirement community residents. Pain Med. 2004; 5: Fishbain DA. Chronic pain and addiction. In: Boswell MV, Cole BE, eds. Weiner's Pain Management: A Practical Guide for Clinicians. 7th ed. New York, NY: Informa HealthCare; 2005: Edlund MJ, et al. Do users of regularly prescribed opioids have higher rates of substance use problems than nonusers? Pain Med. 2007; 8: Gallagher RM, Verma S. Managing pain and comorbid depression: A public health challenge. Semin Clin Neuropsychiatry. 1999;4: Fishbain DA, et al. Evidence-based data from animal and human experimental studies on pain relief with antidepressants: a structured review. Pain Med. 2000;1: Chou R, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10: Federation of State Medical Boards of the United States, Inc. Model policy for the use of controlled substances for the treatment of pain Fishman SM. Responsible Opioid Prescribing: A Physician s Guide. Federation of State Medical Boards of the United States, Inc; Gourlay DL, et al. Universal precautions in pain medicine: a rational approach to the treatment of chronic pain. Pain Med. 2005;6:

8 Multidimensional Issues in Pain Management The Neurobiologic & Pharmacologic Interface of Pain & Psychiatric Disorders It is increasingly recognized that many patients with chronic pain have comorbid psychiatric problems. 1-5 A study utilizing data from the National Comorbidity Survey found that patients with chronic pain were significantly more likely than individuals in the general population to have a coexisting past-year mood disorder (22% vs 10%) or anxiety disorder (35% vs 18%) (Table 1). 1 Similarly, individuals suffering from affective disorders frequently report chronic pain symptoms. 6 In a cohort of almost 6000 primary care patients, among those with current major depressive disorder (MDD), 41% reported disabling chronic pain and 25% reported nondisabling chronic pain. 6 In contrast, among those without MDD, disabling and nondisabling chronic pain were reported in 10% and 33%, respectively. 6 This overlap between pain and psychiatric disorders has implications for treatment, as chronic pain and affective disorders are not necessarily discrete clinical targets, but share some descriptive phenomenology and underlying biology. 3 Regardless of primacy, when each disorder is present, both should be identified and treated. 3,5 The following report highlights the major points raised during a roundtable discussion of this theme led by Michael H. Moskowitz, MD, MPH, Assistant Clinical Professor, Department of Anesthesiology and Pain Medicine, University of California Davis School of Medicine, Sacramento, California, and Bay Area Pain Medical Associates, Mill Valley, California. Mechanisms of Pain Pain is a complex physical and emotional experience that is unpleasant and may represent actual or potential tissue damage. 3,7 Peripheral nerve receptors (nociceptors) transmit sensory signals via afferent fibers into the dorsal horn of the spinal cord, and from there via ascending pathways to higher brain centers where noxious signals are perceived and interpreted. 8 The brain and spinal cord collaborate to perceive the sensation; react to minimize damage to tissue; and dampen the pain sensation via descending modulatory mechanisms in the central nervous system (CNS), even while damaged tissue is healing. 3,9 However, a number of spinal mechanisms modulate the activity of dorsal horn neurons, so the relationship between stimulus and pain response is not always straightforward. 8 Table 1. Prevalence of past-year psychiatric disorders in patients with chronic pain vs the general population 1 Number of participants meeting diagnostic criteria (%) General Chronic pain population Diagnosis (N=382) (N=5495) Any mood disorder 83 (21.7) 551 (10.0) Depression 77 (20.2) 510 (9.3) Dysthymia 20 (5.2) 128 (2.3) Any anxiety disorder 134 (35.1) 992 (18.1) Generalized anxiety disorder 28 (7.3) 144 (2.6) Panic disorder with agoraphobia 25 (6.5) 103 (1.9) Simple phobia 60 (15.7) 456 (8.3) Social phobia 45 (11.8) 428 (7.8) Agoraphobia with or without panic 32 (8.4) 182 (3.3) Posttraumatic stress disorder 41 (10.7) 182 (3.3) In chronic pain, the built-in inhibitory mechanisms that modulate acute pain fail through a process of amplified neuronal activation in the spinal cord and brain, partly because of the phenomenon of central sensitization, or wind-up, which results in abnormal neuroplastic restructuring. 3,8,10 Impairment of the regulatory signal that should counter the pain message produces instead a pain experience (and emotional response) that can be out of proportion, self-sustaining, and independent of peripheral input. 3 In contrast to the normal acute pain response that acts as an alarm system, chronic pain can be considered a disease process of maladaptive neuroplastic changes within the CNS. 11,12 Overlap of Pain and Psychiatric Disorders Chronic pain and psychiatric disorders share many commonalities, ranging from descriptive phenomenology to underlying biology. 3 Pain processing occurs in a number Figure 1. Examples of brain and spinal cord centers that process both pain and emotion 3 Emotion Overlap Brain: Limbic system Hypothalamus Prefrontal cortex Locus ceruleus Spinal cord: Dorsal horn Pain 6

9 of brain areas, resulting in a broad response to chronic pain that includes emotional, neuroendocrine, arousal, autonomic, and somatosensory components. 3,13,14 The processing of pain, mood, and anxiety disorders overlaps in many anatomic areas (Figure 1), and loss of neurochemical homeostasis is a hallmark of these disorders, which can result in, or is the result of, maladaptive neuroplasticity. 3,5 The dysfunctional neuroplasticity and subsequent reduction in neural regulation seen in chronic pain and psychiatric disorders have several areas of overlap; for example: Gamma-aminobutyric acid (GABA) is the chief inhibitory neurotransmitter that regulates pain, sleep, anxiety, and seizure activity. Chronic pain is associated with decreased GABAergic control, leading to hyperexcitation of the CNS through glutamate release. 3 Substance P release at presynaptic terminals can be abnormally increased because of pain, inflammation, depression, and anxiety. 3 N-methyl-D-aspartic acid receptor-activation has a central role in the neuroplasticity of pain and affective disorders. 3,8 Serotonin and norepinephrine (monoamine) center dysfunction is associated with the pathophysiology of depression, anxiety, and chronic pain. 3,4,14-16 Monoamine cells send axonal projections throughout the brain to mediate specific functions, and down the spinal cord, where they determine how the patient reacts to external threats and to sensations associated with routine body functioning. 4 Consciousness of autonomic processes Figure 2. Simultaneous approach to chronic pain and affective disorders 3 such as digestion is suppressed when descending noradrenergic and serotonergic pathways function normally; however, a malfunction that allows routine sensory input to be interpreted as pain could explain why depressed patients exhibit physical symptoms for which no pathology is evident. 4,16 Treatment When managing patients with both pain and mood disorders, physicians may be unable to determine which comorbidity is primary and which is secondary. 3 A strategy that simultaneously assesses and treats mood disorders and pain may optimize outcomes in order to restore quality of life (Figure 2). 3,5 Pharmacotherapy Just as there is significant anatomic, neurochemical, and neurophysiologic overlap between pain and psychiatric disorders, treatment options are also related. 3 In addition to traditional analgesics, neurologic and psychiatric drugs used to treat chronic pain include certain antidepressants (tricyclic antidepressants [TCAs], dual reuptake inhibitors of serotonin and norepinephrine) and anticonvulsants (Figure 3). 3,17-24 These adjuvant agents are often preferred first-line treatments for chronic neuropathic pain. 19 Most adjuvant drugs are used off-label to treat chronic pain. However, 5 adjuvant agents have been approved for pain indications: Carbamazepine: an anticonvulsant, approved for trigeminal neuralgia Figure 3. Overlap of major drug groups used in pain medicine and psychiatry 3 Pain Overlap Psychopharmacology Treat mood disorder Treat pain Use rational polypharmacology Sodium channel blockers NSAIDs Opioids Alphablockers Lithium Beta-blockers Alpha-2-adrenergic agonists Benzodiazepines Antidepressants Antipsychotics Anticonvulsants Stimulants Improved outcome NSAID, nonsteroidal anti-inflammatory drug 7

10 Multidimensional Issues in Pain Management Duloxetine: a dual-action antidepressant that inhibits both norepinephrine and serotonin reuptake, approved for diabetic peripheral neuropathy (DPN) and fibromyalgia Gabapentin: an anticonvulsant, approved for postherpetic neuralgia (PHN) Pregabalin: an anticonvulsant, approved for DPN, PHN, and fibromyalgia Topiramate: an anticonvulsant, approved for migraine headache prevention in adults Treating pain and mood disorders simultaneously often requires an approach of rational pharmacotherapy to achieve the goals of therapy: reduce pain and psychologic symptoms. Factors to consider include individual pathology, sites of action, methods of administration, and patient adherence. 3,19,25 The natural tendency to want to use monotherapy to treat an individual with both these comorbidities can be challenging because of potential differences in dose needed to treat each condition (eg, low-dose TCA may relieve pain, but a higher dose may be needed to treat depression) and because of intolerable adverse effects (AEs) especially if patients are in an amplified state that exaggerates their intolerance of both symptoms and AEs. 3,15 Newer agents such as duloxetine and pregabalin may offer promise as single agents to treat some patients with coexisting pain, anxiety, and depression, but combination therapy with adjuvant and traditional analgesics may be needed for other patients. 3,20,26 The art of treating pain along with psychiatric disorders is based on using a combination of agents that maximizes efficacy, while minimizing AEs and drug-drug interactions. 3 A Biopsychosocial Approach In contrast to the biomedical model, the biopsychosocial approach to medical care considers the interrelatedness of physiologic and psychologic events. 3,27 It is based on the pioneering work of George L. Engel, MD, who described the influence of patients whole-life experiences on the development of heart disease. 3,27 Applying Principles of Neuroplasticity: Although still a field in its infancy, teaching patients to apply the principles of neuroplasticity may help them to self-manage their pain. 9,11,12 In his pain practice, Dr Moskowitz begins by requiring patients to read The Brain That Changes Itself: Stories of Personal Triumph From the Frontiers of Brain Science, by Norman Doidge, MD, in order to understand the concept of neuroplasticity. 11 He uses dramatic visual images of the brain (eg, from functional magnetic resonance imaging) to illustrate the functional regions of the brain that are turned on during the experience of chronic pain. These images can also be used to demonstrate the harmful neuroplasticity that occurs when the pain circuitry expands beyond its usual bounds and recruits neurons/connections from surrounding areas, in effect stealing that function. Because the brain determines what is painful, when peripheral signals do not reach the brain, the individual experiences no pain (eg, used for anesthesia). During acute pain, outlying nerve cells warn of impending danger by initiating signals to the brain, but the brain dispatches descending signals that suppress the unpleasant experience. 3,8,9 In chronic pain, these inhibitory signals do not function efficiently, allowing superexcited nerve cells to invade ever-wider areas of the brain that affect different parts of the body. This results in an expanded chronic pain map, where the brain is not able to quell the pain signal. This neuroplasticity can be considered reversible brain damage. Patients can be taught to take back their connections by consciously focusing on the functional regions of the brain where the pain map has expanded in effect, changing the expanded chronic pain map back to an acute pain map where the brain can inhibit the pain signal without conscious input. Over time, patients learn to counter worsening pain with soothing, pain-fighting, and calming thoughts, emotions, or memories; pleasant sensations; and/or movement, or if movement is impossible because of pain thoughts of movement. This directs the patient s thoughts away from the site of pain sensation to the site of pain perception, the brain itself. Each patient should develop a repertoire of mental techniques to counter sudden signs of increasing pain: short exercises for use when in the company of others, with more elaborate constructs for when one is alone. The object of focusing on pain maps in the brain is to influence their size and formation, and to slow down the overexcited cells that thwart the brain s normal regulatory functions. The intermediate goal of this empowering therapy is to reduce pain; the ultimate goal is to restore a benign neuroplasticity to the brain that is, to increase the normally functioning areas of the brain 8

11 by decreasing or stealing back neurons from the dysfunctional regions, thereby restoring the brain s ability to turn off the pain. Conclusion There is significant neurobiologic and pharmacologic overlap between chronic pain and psychiatric disorders. Patients with coexisting problems will likely benefit from an approach of rational polypharmacology and biopsychosocial medical care. References 1. McWilliams LA, et al. Mood and anxiety disorders associated with chronic pain: an examination in a nationally representative sample. Pain. 2003;106: Baliki MN, et al. Beyond feeling: chronic pain hurts the brain, disrupting the default-mode network dynamics. J Neurosci. 2008;28: Moskowitz M, Fishman SM. The neurobiological and therapeutic intersection of pain and affective disorders. Focus Psychiatry Online. 2006;4: Stahl SM. Does depression hurt? J Clin Psychiatry. 2002;63: Bair MJ, et al. Depression and pain comorbidity: a literature review. Arch Intern Med. 2003;163: Arnow BA, et al. Comorbid depression, chronic pain, and disability in primary care. Psychosom Med. 2006;68: Merskey H, Bogduk N, eds. Classification of Chronic Pain. Seattle, WA: IASP Press; D Mello R, Dickenson AH. Spinal cord mechanisms of pain. Br J Anaesth. 2008;101: Fishman S, Berger L. The War on Pain. New York, NY: HarperCollins Publishers; Woolf CJ, Salter MW. Plasticity and pain: role of the dorsal horn. In: McMahon SB, Koltzenburg M, eds. Wall and Melzack s Textbook of Pain. 5th ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2006: Doidge N. The Brain That Changes Itself: Stories of Personal Triumph from the Frontiers of Brain Science. New York, NY: Viking Penguin; Siegel GJ, et al, eds. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 7th ed. London, England: Elsevier Academic Press; Price DD. Psychological and neural mechanisms of the affective dimension of pain. Science. 2000;288: Price DD. Psychological Mechanisms of Pain and Analgesia (Progress in Pain Research and Management, V. 15). Seattle, WA: IASP Press; Wise TN, et al. Painful physical symptoms in depression: a clinical challenge. Pain Med. 2007;8(suppl 2):S Stahl SM. The psychopharmacology of painful physical symptoms in depression. J Clin Psychiatry. 2002;63: McCleane G. Antidepressants as analgesics. CNS Drugs. 2008;22: Ettinger AB, Argoff CE. Use of antiepileptic drugs for nonepileptic conditions: psychiatric disorders and chronic pain. Neurotherapeutics. 2007;4: Dworkin RH, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain. 2007;132: Watson CPN, et al. Antidepressant analgesics: a systematic review and comparative study. In: McMahon SB, Koltzenburg M, eds. Wall and Melzack s Textbook of Pain. 5th ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2006: Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007;(4):CD Zin CS, et al. An update on the pharmacological management of postherpetic neuralgia and painful diabetic neuropathy. CNS Drugs. 2008; 22: Brecht S, et al. Efficacy and safety of duloxetine 60 mg once daily in the treatment of pain in patients with major depressive disorder and at least moderate pain of unknown etiology: a randomized controlled trial. J Clin Psychiatry. 2007;68: Johannessen LC. Antiepileptic drugs in non-epilepsy disorders: relations between mechanisms of action and clinical efficacy. CNS Drugs. 2008;22: Moskowitz MH. Pharmacotherapy of neuropathic low back pain. Curr Pain Headache Rep. 2003;7: Stahl SM. Anticonvulsants and the relief of chronic pain: pregabalin and gabapentin as alpha(2)delta ligands at voltage-gated calcium channels. J Clin Psychiatry. 2004;65: Engel GL. The clinical application of the biopsychosocial model. Am J Psychiatry. 1980;137:

12 Technologies & Practices to Manage Risk Emerging Pharmaceutical Strategies to Reduce Opioid Abuse in Pain Management Clinical Utility of New Opioid Formulations With Potential to Deter Abuse Urine Drug Testing in Pain Medicine: Pearls & Pitfalls Disclosures: Lynn R. Webster, MD, reports Consultant Honoraria: Boston Scientific Corporation, Cephalon, Inc, Elan Pharmaceuticals, Inc, Medtronic, Inc, King Pharmaceuticals, Ameritox, Ltd Research Grants: Abbott Laboratories, Advanced Bionics Corporation, Ameritox, Ltd, AstraZeneca Pharmaceuticals, CoMentis Inc, DURECT Corporation, Elan Pharmaceuticals, Inc, Forest Pharmaceuticals, Inc, GlaxoSmithKline plc, Jazz Pharmaceuticals, Inc, King Pharmaceuticals, Medtronic, Inc, Merck & Co, Inc, Nektar Therapeutics, NeurogesX, Inc, Purdue Pharma, LP, QRxPharma, Respironics, Inc, Takeda Pharmaceutical Company Limited, TorreyPines Therapeutics, Wyeth, ZARS Pharma, Inc Advisory Board Honoraria: Ameritox, Ltd, King Pharmaceuticals, Nektar Therapeutics, Nervo, Neuromed Pharmaceuticals Ltd, Purdue Pharma, LP. Steven D. Passik, PhD, reports Grant, Consultant/Speaker: Cephalon, Inc, Ligand Pharmaceuticals, Inc Consultant/Speaker: Eli Lilly and Company, PRICARA, King Pharmaceuticals. Howard A. Heit, MD, reports Consultant: MEDA Pharmaceuticals, Alpharma Pharmaceuticals LLC, Endo Pharmaceuticals Speaker: Purdue Pharma, LP Canada Consultant/Speaker: Purdue Pharma, LP, Abbott Laboratories, Cephalon, Inc, Titan Pharmaceuticals, King Pharmaceuticals. Douglas L. Gourlay, MD, reports that he has no financial relationships with any commercial entities that produce health care related products and/or services. 10

13 Emerging Pharmaceutical Strategies to Reduce Opioid Abuse in Pain Management Opioid analgesics, though essential to manage pain in certain patients, are among the most frequently misused and abused prescription drugs in the United States. 1,2 Reluctance to prescribe these drugs when they are appropriately indicated can contribute to the prevalence of undertreated pain. 3-5 Management of the public health issues related to opioid misuse and abuse requires a balanced effort among stakeholders at the federal, state, industry, payor, and practitioner levels. 4,6 As one strategy to minimize some of the harms associated with opioid treatment, while at the same time maintaining appropriate access to legitimate therapy, pharmaceutical companies are developing novel abuse-deterrent opioid formulations. 4,6-9 Lynn R. Webster, MD, Medical Director of Lifetree Clinical Research and Pain Clinic, Salt Lake City, Utah, led a roundtable discussion about the benefits and limitations of emerging pharmaceutical agents that are being developed with features designed to help avert misuse. An ideal opioid formulation would provide effective analgesia, with minimal to no potential for: 6,7 Adverse effects (AEs) if ingested in excess Withdrawal Tolerance Hyperalgesia Reward-seeking behavior Craving Addiction Types of Abuse-Deterrent Opioid Technology Prescription opioid misuse encompasses a wide spectrum of motives and behaviors, both of which can change over time All products are vulnerable to being ingested intact to excess, and many of the currently available extendedrelease (ER) opioid products are susceptible to dumping a large dose when the product is tampered with in an effort to modify the opioid delivery. 6,9 The various new abusedeterrent formulations will target one or more common types of opioid misuse. 7,8,12-14 The goal is to reduce misuse without compromising analgesia or causing new AEs for patients taking then legitimately for pain, and without creating unacceptable risks for potential abusers. 4,6,7,9 Physical Barriers A number of opioid formulations in development make use of physical barriers to prevent common methods of tampering simple physical manipulation (eg, chewing, crushing), single-step chemical manipulations (eg, dissolving in water or alcohol), multistep chemical manipulations (eg, dissolving in alcohol and then redissolving in water), and laboratory extractions. 7 One ER opioid formulation uses viscous gel-cap technology to thwart attempts to defeat the ER mechanism by forcing release of an entire 12-hour dose at once to bring about an intense drug high. 12,13 The capsule in this formulation resists crushing and dissolution in alcohol or water, or other means of preparing the drug in a form conducive for intranasal (IN) or intravenous (IV) use. 13 Development of a product with limited extractability by alcohol is important, because the US Food and Drug Administration is increasingly concerned about dangerous increases in plasma opioid concentrations or dose dumping when opioids are coingested with alcohol, whether deliberately or inadvertently Formulations employing physical barriers may help reduce several forms of misuse, but they cannot prevent the ingestion of excessive amounts of intact product. 7,13,14 Agonist-Antagonist Combinations Another strategy to deter tampering with an opioid is to incorporate an opioid antagonist (eg, naltrexone) into an ER opioid formulation, either sequestered in the core or added as a nonabsorbable component. 6,9,12,14 When taken intact, the opioid agonist is released steadily into the body with no or little absorption of the antagonist, thereby still providing the desired therapeutic analgesic effect. 6,7,9,12,14 However, crushing/grinding the preparation or dissolving it in a liquid in an attempt to extract the full dose at once is expected to release the antagonist at doses sufficient to counteract the opioid effects (including euphoria), and possibly precipitate withdrawal in physically dependent persons. 7,9,12,14,16 Again, although this technology may decrease the likelihood of chewing and IN/IV use of the crushed/dissolved opioid, it is unlikely to prevent overuse of intact medication. 6,7 Also, determined abusers may develop methods, depending upon specific formulation design, to selectively extract the opioid. 9 An alternative approach utilizing the opioid agonistantagonist strategy is to combine an immediate-release (IR) opioid with an ultralow-dose antagonist this method, while providing equivalent analgesia, may help reduce or 11

14 Technologies & Practices to Manage Risk slow the development of physical dependence compared with use of an opioid alone. 6,17,18 Although the mechanism of action is not fully understood, modulation of the mu-opioid receptor is implicated. 6,18 Whether opioid formulations combined with an ultralow-dose antagonist will adequately relieve the most severe types of chronic pain is unknown. 6 Their ability to reduce abuse-liability of the opioid is under investigation. 6 Aversive Components Components that produce unpleasant effects can be incorporated into opioid formulations to help discourage manipulation of the formulation and/or excessive use. 6,7 For example, an IR opioid formulation in development contains a subtherapeutic amount of niacin. 7,14 At the recommended dose, the niacin causes no AEs; however, users ingesting a larger amount may experience unpleasant niacin-induced flushing, chills, sweating, and headache. 7,14 Such a formulation, if successful, will likely be beneficial in preventing overuse of the intact opioid medication. 7,14 In addition, this formulation transforms into a viscous gel when dissolved in water or alcohol, making it difficult to extract the opioid or to inject it. 19 If these tablets are crushed and snorted, a mild burning and irritation of nasal passages is expected, and moisture in the nasal passages will cause formation of a viscous gel. 19 Capsaicin is also under consideration as an irritant to compound with an opioid agonist. 6,7,17,20 No AEs would occur when the capsaicin-opioid formulation is ingested whole as directed, but chewing or crushing it would release the capsaicin, causing an intense burning sensation. 6,7,20 Sequestering an emetic within an opioid formulation is another potential aversive abuse-deterrent approach the emetic would induce vomiting if the delivery system was altered. 6 Questions remain as to what extent opioid formulations that incorporate aversive components or irritants will induce AEs in patients who take them as directed, or in those who unwittingly misuse them by chewing or splitting the product prior to oral ingestion. 7 Prodrugs A prodrug has little to no pharmacologic effect until it is metabolized to an active form. 7 One prodrug technology that has been considered in abuse-deterrent formulations employs the amino acid lysine to modify an IR opioid. 7,12 When the opioid is ingested orally, enzymes in the gastrointestinal (GI) tract cleave the lysine, activating the opioid. 7,12 If the GI tract is bypassed, however via IV or IN use the opioid should remain inactive. 7,12 In addition, the need for an enzymatic step in the biotransformation of a prodrug to an active opioid may be rate limiting, reducing the risk from overdose. 12 Routes of Administration Some opioid products may be abused less frequently because it is more difficult to extract the drug. 7 For example, transdermal fentanyl is abused at a rate lower than that of other ER opioids because it is difficult for abusers to extract a rapid-onset, supratherapeutic, yet nonlethal, dose of opioid from the patch. 7 Other delivery systems in development show even more promise; for example, a subcutaneous implant would release opioid continuously over several months. 7 Reducing Drug Reward The rewarding or euphoric properties of opioids, commonly described in terms of a dopamine surge, involves a complex cascade of events influenced by many factors. 17 Research is ongoing to target molecular and intracellular mechanisms that interrupt these events in order to prevent reward, as well as other effects, such as tolerance, craving, and hyperalgesia. 17 Practical Considerations The ability for new opioid formulations to effectively reduce misuse and abuse will require technically successful designs, widespread market penetration, and appropriate evaluation both in postmarketing epidemiologic studies and systematically in large clinical trials. 7,13 However, even successful new preparations will be unlikely to realize their full potential public health benefits until earlier-generation opioids become relatively unavailable. 7 Factors to consider when assessing a new opioid abuse-deterrent formulation include: 13 Who is likely to abuse the drug? Can it be abused without manipulation? Are there potential methods of altering/compromising the ER mechanism, or of extracting the active ingredient? Are alternate routes of administration possible? What are the effects of multiple doses? Is there potential for abuse (or additional AEs) in combination with other substances, especially alcohol? 12

15 Table 1. Eight guidelines for physicians to observe when prescribing opioids 22 1 Assess patients for risk of abuse before opioid therapy and manage accordingly 2 Watch for and treat comorbid mental disease when it occurs 3 Use conventional conversion tables cautiously when rotating (switching) from one opioid to another 4 Avoid combining benzodiazepines with opioids, especially during sleep hours 5 Methadone should be started at a very low dose and titrated slowly regardless of whether the patient is opioid tolerant or not 6 Assess for sleep apnea in patients on high daily doses of methadone or other opioids and in patients with a predisposition 7 Tell patients on long-term opioid therapy to reduce opioid dose during upper respiratory infections or asthmatic episodes 8 Avoid using long-acting opioid formulations for acute postoperative or trauma-related pain Table 2. Six steps for patients to follow when using opioid analgesics 22 1 Never take a prescription painkiller unless it is prescribed to you 2 Do not take pain medicine with alcohol 3 Do not take more doses than prescribed 4 Use of other sedative or anti-anxiety medications can be dangerous 5 Avoid using prescription painkillers to facilitate sleep 6 Lock up prescription painkillers Everyone responds differently to pain medications. What is safe for one person may not be safe for another. Never mix the two; it is a dangerous combination that can be deadly. Alcohol increases the toxicity of pain medication. Even after the effects of pain medicine seem to have worn off, the drug is still depressing the respiratory system. The body must develop a tolerance to the respiratory depressant effects before the dose can be increased. Combining pain medicines with other sedative drugs, such as valium, can increase the toxicity of the pain medication. Only take other medications if directed by the prescribing doctor. Prescription pain medications can suppress respiration during sleep. Speak to your physician about safe methods to manage pain during sleep. If consumed by children or other family members, or stolen and sold on the street, prescription pain medicine can kill. Above all, it is essential that these new formulations maintain analgesic efficacy, pose no added risks for legitimate patients who use them as indicated, and create no unacceptable risks for abusers. 9 Additionally, even if effective, new formulations targeting misuse and abuse are only one aspect of a comprehensive approach to prescription opioid risk management. 7,9,13,21 Zero Unintentional Deaths is a national campaign of LifeSource, a nonprofit foundation, to reduce prescription drug misuse and eliminate unintentional overdose, without compromising access to pain treatment. 22 The campaign provides 8 guidelines for physicians to observe when prescribing opioids and other psychotherapeutics (Table 1), as well as 6 steps for patients to follow when taking prescribed opioids (Table 2). 22 Conclusion No single product will protect patients from irresponsible use of the medication, and individuals determined to abuse opioids will likely find methods to circumvent new technologies. 7,9,13,21 Although an ideal opioid does not exist currently, new abuse-deterrent formulations already in development have potential to combat elements of the prescription opioid abuse problem while addressing pain. 6,7,17 Many of the benefits will likely be product-specific to the type of abuse deterred. 6-9,12-14,17 References 1. National Institute on Drug Abuse. Prescription Drugs: Abuse and Addiction. NIH Publication No Rockville, MD: US Department of Health and Human Services, National Institutes of Health; Substance Abuse and Mental Health Services Administration, Office of Applied Studies. Results from the 2007 National Survey on Drug Use and Health. National Findings. NSDUH Series: H-34, DHHS Publication No. (SMA) Rockville, MD Federation of State Medical Boards of the United States, Inc. Model policy for the use of controlled substances for the treatment of pain Katz NP, et al. Foundations of opioid risk management. Clin J Pain. 2007;23: Fishman SM. Risk of the view through the keyhole: there is much more to physician reactions to the DEA than the number of formal actions. Pain Med. 2006;7: Webster LR. Emerging research on abuse-deterrent opioids. In: Webster LR, Dove B. Avoiding Opioid Abuse While Managing Pain: A Guide for Practitioners. North Branch, MN: Sunrise River Press; 2007:

16 Technologies & Practices to Manage Risk 7. Katz N. Abuse-deterrent opioid formulations: are they a pipe dream? Curr Rheumatol Rep. 2008;10: Katz NP, et al. Challenges in the development of prescription opioid abuse-deterrent formulations. Clin J Pain. 2007;23: Fudala PJ, Johnson RE. Development of opioid formulations with limited diversion and abuse potential. Drug Alcohol Depend. 2006;83(suppl 1):S Webster LR. A retrospective review of initial motives for seeking opioids as reported by patients being treated for opioid addiction. Presented at: 24th Annual Meeting of the American Academy of Pain Medicine; February 12-16, 2008; Orlando, FL. Poster # Passik SD, et al. Psychiatric and pain characteristics of prescription drug abusers entering drug rehabilitation. J Pain Palliat Care Pharmacother. 2006;20: Gershell L, Goater JJ. Making gains in pain. Nat Rev Drug Discov. 2006;5: Webster LR. PTI-821: sustained-release oxycodone using gel-cap technology. Expert Opin Investig Drugs. 2007;16: Lavine G. Abuse deterrence focus of upcoming opioid formulations. Am J Health Syst Pharm. 2008;65:381, US Food and Drug Administration. FDA Alert [07/005]: Alcohol- Palladone Interaction Jones JB, et al. ALO-01, an investigational extended-release opioid formulation containing morphine sulfate and sequestered naltrexone: Pharmacodynamic (drug liking) effects. Presented at: 24th Annual Meeting of the American Academy of Pain Medicine; February 12-16, 2008; Orlando, FL. Poster # Webster LR. Emerging solutions for avoiding opioid abuse while managing pain. Pain Pract. 2007;17: Webster LR, et al. Oxytrex minimizes physical dependence while providing effective analgesia: a randomized controlled trial in low back pain. J Pain. 2006;7: Acura Pharmaceuticals, Inc. Aversion Technology Cromie WJ. Using chili peppers to burn drug abusers. Harvard University Gazette. December 21, Cone EJ. Ephemeral profiles of prescription drug and formulation tampering: evolving pseudoscience on the Internet. Drug Alcohol Depend. 2006;83(suppl 1):S LifeSource. Zero Unintentional Deaths. Clinical Utility of New Opioid Formulations With Potential to Deter Abuse Novel opioid formulations in development with abusedeterrent properties are intended to help decrease opioid misuse and abuse. 1-3 A roundtable discussion about the clinical utility of abuse-deterrent prescription opioids was led by Steven D. Passik, PhD, Associate Attending Psychologist, Memorial Sloan-Kettering Cancer Center, New York, New York. Like most clinicians who trust that patients seek help from them in good faith, the majority of attendees believed that their patient population was not abusing prescription drugs. 4 However, patients sometimes mislead prescribers to obtain more opioids, and may abuse or divert their medication without the physician s knowledge. Dr Passik reviewed data that is beginning to shed light on the extent of prescription drug misuse in the clinical setting. 4,5 A prospective survey of prescription drug abusers entering a treatment facility found the majority (84%) had legitimately been given an opioid prescription for pain at some point from a physician, and that 61% reported chronic pain concerns. 6 At the minimum, rates of addiction and abuse among chronic pain patients exposed to opioids are as high as in the general population. 7 Risk of Abuse Clinical observations of and self-reported drug use by chronic pain patients can be unreliable. 8 A study in primary care patients receiving daily opioid therapy (n=771) found significant underreporting of drug use compared with self-report, urine drug testing (UDT) identified 50 additional patients with marijuana exposure (156 vs 106) and 34 additional patients with cocaine exposure (60 vs 26). 8 During the research interview, 46% of patients with positive UDT results denied illicit drug use, even when they were guaranteed anonymity. 8 Among patients prescribed opioids in an urban pain management setting, UDT also reveals a high incidence (45%) of abnormal findings, which was not predicted by patient descriptors (other than age) or by the number, type, and dose of prescribed opioid. 9 UDT in combination with behavior monitoring of patients on chronic opioid therapy detects more individuals with aberrant drug-related behaviors (ADRBs) than either method alone, so to better capture the incidence of addiction and ADRBs in patients on chronic opioid therapy, physicians should routinely monitor both ADRB and UDT results. 10,11 14

17 Table 1. Aberrant drug-related behaviors that suggest a potential substance use disorder 17 More predictive Sell prescription drugs Prescription forgery Steal or borrow drugs Inject oral formulation Obtain prescription drugs from nonmedical sources Concurrent alcohol/illicit drug abuse Multiple dose escalations or other noncompliance despite warnings Multiple episodes of prescription loss Repeatedly seek prescriptions from other clinicians or emergency department despite warnings Less predictive Aggressively complain about need for more drugs Hoard drugs during periods of reduced symptoms Request specific drugs Openly acquire similar drugs from other medical sources Unsanctioned dose escalation or other noncompliance once or twice Unapproved use to treat another symptom Report psychic effects not intended by clinician A systematic review of 24 studies with 2507 pain patients on chronic opioid therapy revealed that if patients are selected carefully for no prior history of substance abuse, low rates of addiction (0.19%, compared with 3.27% overall) and ADRBs (in 17 studies, 0.59%, compared with 11.5% overall) are reported. 11 Again, the prevalence of ADRBs identified by UDT (in 5 studies, 20.4%) was higher than that identified by observation only (11.5%). 11 Risk Assessment Physicians must conduct a thorough medical evaluation and addiction/abuse risk assessment prior to prescribing opioids in order to accommodate that risk into the patient s treatment plan or to determine who would not benefit from opioid therapy. 6,12,13 Several clinical tools have been developed to help practitioners predict the risk of ADRBs emerging in pain patients. 7 Three examples are the Screener and Opioid Assessment for Patients with Pain (SOAPP ), the Opioid Risk Tool (ORT ), and the Screening Instrument for Substance Abuse Potential (SISAP). 7,14-16 The SOAPP may be particularly effective in high-risk settings, while the ORT a brief 5-question measure to classify a patient as high, medium, or low risk for misusing opioids prescribed for pain may be better suited to settings that have a predominantly low-risk patient population. 7,14 The SISAP is also a 5-item questionnaire designed to identify pain patients at risk of abusing opioids, particularly those who use illicit drugs or consume large amounts of alcohol. 7,15 Classification of a patient as high-risk for potential substance abuse does not contraindicate opioid therapy, which may be justified if pain is significant, if other treatments are unsatisfactory, and with the understanding that opioid use is carefully monitored. Assessment of risk factors can help physicians establish safeguards and structure the treatment approach to potentially enable at-risk patients to experience beneficial outcomes. Type of Abuse ADRBs refer to a range of events involving prescribed opioid medication that suggest a potential substance use disorder (Table 1). 17 A few ADRBs are blatant (eg, forging prescriptions), but most are more ambiguous yellow flags (eg, occasional dose escalation or medication use to treat psychologic disorders such as anxiety). 18,19 Requests for early renewals of opioid prescriptions is one of the most frequent ADRBs. 20 The number of ADRBs reported for a patient is associated with the potential for a current substance use disorder. Among a population of primary care patients receiving opioids for chronic pain, only 1% of patients with 1 to 3 lifetime ADRBs met criteria for current opioid use problems, compared with 10% of those reporting 4 or more behaviors; any substance use disorders were reported in 5% and 24% of patients in these groups, respectively. 17 Differential diagnoses to consider when interpreting ADRBs are shown in Table 2. 19,21 Serious ADRBs, such as changing the route of administration, are more commonly seen in recreational users and addicts rather than pain patients. 5 However, one study of patients in a substance abuse treatment facility found that on admission, 8 of 60 pain patients (13%) disclosed injecting controlled-release oxycodone. 5 The majority of the controlled-release oxycodone-abusing patients in this study (regardless of pain) had initially abused the drug orally (83%). 5 By the time of admission, snorting (58%) had become the primary route of administration, followed by oral (21%) and intravenous (IV) use (21%). 5 Another study of patients admitted to substance abuse programs for Table 2. Differential diagnoses of aberrant drug-related behaviors 19,21 Addiction (out-of-control, compulsive drug use) Pseudoaddiction (inadequate analgesia) Other psychiatric diagnosis Organic mental syndrome (confused, stereotyped drug-taking) Personality disorder (impulsive, entitled, chemical-coping behavior) Chemical coping (drug overly central) Depression/Anxiety/Situational stressors (self-medication) Criminal intent (diversion) 15

18 Technologies & Practices to Manage Risk Figure 1. Progression of problematic opioid-related behaviors in pain management Dosing out of schedule Compromising delivery system (chewing) Altering administration route (intranasal) Altering administration route (intravenous) prescription drug abuse also found that most began with oral administration, but shifted to intranasal or IV administration over time (Figure 1). 6 However, a large proportion of substance abusers does not alter the delivery system, but overuses intact tablets. 22 Addressing Risk With New Formulations Novel abuse-deterrent opioid formulations have the potential to reduce prescription opioid abuse within a comprehensive program of screening and individualized treatment. 3 A variety of abuse-deterrent strategies are needed to protect the heterogeneous population of patient and nonpatient misusers, because a product that deters one type of abuse (eg, chewing or crushing) might not be effective against another type (eg, overusing intact tablets). 1-3,13,23 Summary Ultimately, abuse-deterrent opioid formulations may have clinical utility as part of but not in place of a multistrategy clinical risk management package that includes: Screening and risk stratification Observation of patient behavior Use of prescription monitoring program data (where available) Compliance monitoring (eg, UDT, pill/patch counts) Patient education about drug storage and sharing Psychotherapy and highly structured approaches (when needed) References 1. Gershell L, Goater JJ. Making gains in pain. Nat Rev Drug Discov. 2006;5: Katz NP, et al. Challenges in the development of prescription opioid abuse-deterrent formulations. Clin J Pain. 2007;23: Katz N. Abuse-deterrent opioid formulations: are they a pipe dream? Curr Rheumatol Rep. 2008;10: Passik SD, Kirsh KL. Commentary on Jung and Reidenberg s Physicians being deceived : aberrant drug-taking behaviors: what pain physicians can know (or should know). Pain Med. 2007;8: Hays L, et al. Seeking drug treatment for OxyContin abuse: a chart review of consecutive admissions to a substance abuse treatment facility in Kentucky. JNCCN. 2003;1: Passik SD, et al. Psychiatric and pain characteristics of prescription drug abusers entering drug rehabilitation. J Pain Palliat Care Pharmacother. 2006;20: Passik SD, et al. Addiction-related assessment tools and pain management: Instruments for screening, treatment planning, and monitoring compliance. Pain Med. 2008;9(s2):S Fleming MF, et al. Substance use disorders in a primary care sample receiving daily opioid therapy. J Pain. 2007;8: Michna E, et al. Urine toxicology screening among chronic pain patients on opioid therapy: frequency and predictability of abnormal findings. Clin J Pain. 2007;23: Katz NP, et al. Behavioral monitoring and urine toxicology testing in patients receiving long-term opioid therapy. Anesth Analg. 2003; 97: Fishbain DA, et al. What percentage of chronic nonmalignant pain patients exposed to chronic opioid analgesic therapy develop abuse/addiction and/or aberrant drug-related behaviors? A structured evidence-based review. Pain Med. 2008;9: Passik SD, Webster LR. Pain and addiction interface. Pain Med. 2008; 9: Passik SD, Kirsh KL. The interface between pain and drug abuse and the evolution of strategies to optimize pain management while minimizing drug abuse. Exp Clin Psychopharmacol. 2008;16: Webster LR, Webster RM. Predicting aberrant behaviors in opioidtreated patients: Preliminary validation of the Opioid Risk Tool. Pain Med. 2005;6: Coambs RB, et al. The SISAP: A new screening instrument for identifying potential opioid abusers in the management of chronic nonmalignant pain within general medical practice. Pain Res Manag. 1996;1: Butler SF, et al. Validation of the revised Screener and Opioid Assessment for Patients With Pain (SOAPP-R). J Pain. 2008;9: Fleming MF, et al. Reported lifetime aberrant drug-taking behaviors are predictive of current substance use and mental health problems in primary care patients. Pain Med. 2008;9: Portenoy RK. Opioid therapy for chronic nonmalignant pain: a review of the critical issues. J Pain Symptom Manage. 1996;11: Savage SR, et al. Challenges in using opioids to treat pain in persons with substance use disorders. Addict Sci Clin Pract. 2008;4: Passik SD, et al. Monitoring outcomes during long-term opioid therapy for noncancer pain: results with the Pain Assessment and Documentation Tool. J Opioid Manag. 2005;1: Passik SD, Kirsh KL. Assessing aberrant drug-taking behaviors in the patient with chronic pain. Curr Pain Headache Rep. 2004;8: Kirsh KL, et al. Initial development of a survey tool to detect issues of chemical coping in chronic pain patients. Palliat Support Care. 2007; 5: Katz NP, et al. Foundations of opioid risk management. Clin J Pain. 2007;23:

19 Urine Drug Testing in Pain Medicine: Pearls & Pitfalls Urine drug testing (UDT) is a consensual diagnostic test that is performed with full explanation to and for the benefit of the pain patient as part of comprehensive care. 1,2 Roundtable discussions led by Howard A. Heit, MD, Georgetown University School of Medicine, Washington, DC, and Douglas L. Gourlay, MD, Wasser Pain Management Centre, Mount Sinai Hospital, and the Addiction Medicine Clinic, Centre for Addiction and Mental Health, Toronto, Ontario, Canada, reviewed how, when used with an appropriate level of understanding, UDT can improve patient care and reduce risk. Not all pain patients treated with controlled substances have an adequate treatment response, and patients who may suffer from concurrent substance use disorders present challenges to physicians. 3 UDT is used to provide objective documentation of adherence to the mutually agreed-upon treatment plan, aid in the diagnosis and treatment of the disease of addiction and, where it exists, substance misuse, or to advocate for the patient in family and social issues. 1,2 Substances Detected UDT can detect many parent drugs and/or their metabolites in urine, and therefore demonstrates recent use of many prescription medicines or illicit substances. 1,2 For most clinical purposes, initial testing is done with classspecific immunoassay drug panels, which typically do not identify individual drugs within a class. 1,2 Although routinely performed by testing laboratories, point-of-care (POC) devices are also available. Regardless of setting, immunoassays also may not reliably detect all members of a drug class unless a specific test is directed toward the particular parent compound or metabolite. 1,2 For example, opiate immunoassays are designed to detect the naturally occurring opiates morphine and codeine (Table 1), although semisynthetic opioids may be inconsistently detected because of cross-reactivity. 1,2 Certain synthetic Table 1. Source of opioid analgesics 1 Natural Semisynthetic Synthetic (extracted from opium) (derivatives of opium) (man-made) codeine hydrocodone meperidine morphine oxycodone fentanyl series thebaine hydromorphone propoxyphene oxymorphone methadone buprenorphine and semisynthetic opioids, such as methadone or oxycodone, can be tested for by using a specific immunoassay. Following immunoassay, a more specific laboratory-based technique (gas chromatography/mass spectrometry is one of the gold standards) is performed to reliably identify or confirm the presence or absence of a specific drug and/or its metabolite(s). 1,2 In contrast to forensic testing, in which the majority of the population are expected to be negative for drug classes of abuse, adherence/compliance testing requires identification of the specific drug that is causing the positive result, not just drug-class identification. The reason is that the test may be positive for the wrong reason ; that is, a positive opiate immunoassay in a patient prescribed hydromorphone may actually be due to morphine in the urine. Tests offered by different laboratories can vary in a number of respects: for example, the drugs included in the test menu, cross-reactivity patterns, cut-off concentrations above which the test is reported positive, and drug interferences. Correct interpretation of UDT results requires knowledge of these variables. 1,2 A strong working relationship with the testing laboratory personnel (eg, toxicologist, laboratory director) is helpful to learn what can and cannot be reasonably expected of a particular test or laboratory, and to accurately interpret UDT results. 1,2 When selecting a laboratory or POC device manufacturer, physicians are encouraged to ensure that readily accessible consultation and result interpretation services are provided. Point-of-care Testing Several single-use immunoassay devices, without the need for laboratory instrumentation, are commercially available for POC testing of common classes of misused drugs, and certain specific drugs, such as methadone or oxycodone. 1,4 However, these tests do not take the place of laboratory confirmation/identification testing, and POC immunoassay in isolation is often inadequate in clinical practice when the physician is looking to identify the presence of a specific drug or metabolite. Although a POC device can have a rapid turnaround time, there can be a limited test menu, and devices vary in accuracy of analytic performance, sensitivity/ specificity, cross-reactivity, reproducibility, and ease of use. Tests performed outside the traditional laboratory may also lack quality assurance and suffer from data management issues. Results from POC UDT (or any other kind of UDT) should not be used as the sole basis for major decisions in patient care, but as a way to open up a discussion with the patient as to the next step to be taken. 17

20 Technologies & Practices to Manage Risk Testing Strategy A testing strategy encompasses why a test is being ordered, for whom the test is ordered, the results that are obtained, and most importantly, how the results will be used. A pain practice should have a consistent protocol for selecting patients for UDT for example, new patients already receiving a controlled substance, an existing patient being considered for a controlled substance, when making major changes in therapy, and annual random testing on all lowrisk patients. More frequent testing is determined by clinical judgment on a case-by-case basis; for example, if the patient has displayed aberrant behavior, test as often as necessary to document that the patient is adhering to the mutually agreed-upon treatment plan. A provision for UDT can be included in an opioid treatment agreement. In order to reduce stigma, explain to the patient the benefits of UDT, the practice s consistent protocol for performing UDT (rather than relying on patient demographics), and that frequency of testing is based on clinical judgment according to best clinical practices. A history of substance misuse does not preclude appropriate treatment with any medication when indicated (including a controlled substance), but does require a treatment plan with firmly defined boundaries. 1 Interpreting UDT Results Physicians should document UDT results and interpretation in the medical record. 1,2 UDT can only assess the presence or absence of a particular drug and/or metabolite within a specific concentration at a specific moment in time. A positive result does not diagnose drug addiction, physical dependence, or current impairment. Nor does an inappropriate positive or negative UDT result indicate that the patient does not have chronic pain. 3 False-positive or false-negative results can occur, so it is important to interpret UDT carefully and to check for legitimate reasons for an unexpected result. 1,2 Consultation with the laboratory for help interpreting the result is required and the patient should be contacted to explore possible explanations physicians should ask about all drug use, including over-the-counter agents, and time of last use (patients should be required to report any new medication use to the physician). 1,2 Instruct patients not to eat food products containing poppy seeds, because they can lead to true-positive opiate UDT results for several hours after consumption. 1,5 Adherence/Compliance Testing One or a combination of the following occurrences may lead to not detecting a prescribed medication in the patient s urine: 1 The patient did not use the medication The patient has not recently used the medication The test was not sufficiently sensitive to detect the medication at the concentration present Clerical error caused a positive UDT result to be reported as negative A negative result may lead to concerns about misuse by the patient (ie, escalating dose leading to running out, bingeing, or diversion). 1 Any aberrant behavior needs to be addressed in a therapeutic context. 1 Physicians should consult with the laboratory to clarify unexpected negative results; for example, was the result just below the cut-off level of reporting? The most appropriate use of a negative result for a prescribed medication is to initiate a dialog with the patient to determine the cause. 1 Positive UDT results do not provide enough information to determine exposure time, dose, or frequency of use, and at the present time there is no scientifically validated relationship between the amount of drug taken and urine drug concentration. 1 Quantitative determination (ng/dl) by UDT of a drug and/or its metabolite(s) should not be used to extrapolate back and make specific determinations regarding ingestion of the prescribed controlled substance. Even when protocols calculate a normalized value based on patient height/weight, specimen ph and specific gravity, and prescription dosage, numerous other factors that may not be static can affect the absorption, distribution, metabolism, and elimination of a drug. 1 Interpreting UDT results beyond the current scientific knowledge may put physicians and patients at medical and/or legal risk. 1,6,7 Opioid Metabolism Drug metabolism can explain the presence of a variety of compounds found in urine. For example, opioid metabolism may explain the presence of apparently unprescribed opioid medications detected by UDT (Figure 1): Codeine is metabolized to morphine, so both substances may occur in urine following codeine use. A codeine prescription does not normally explain the presence of only morphine (unless the sample is collected 2 to 3 days after last ingesting codeine) 1,2 18