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March 5, 2007 to March 6, 2007
National Institutes of Health, Bethesda, Maryland

Introduction

Nora D. Volkow, M.D.
Director
National Institute on Drug Abuse

This meeting is a direct response to our growing concern about the increased abuse of prescription pain medications, which, when abused, can be life-threatening. Although the latest national surveys show a declining trend in the abuse of licit and illicit substances, prescription pain medication abuse is a growing adolescent problem, ranking second only to marijuana as the most frequently abused substance among 12th-graders. Through this cross-disciplinary meeting, we hope to identify areas where research is needed to build a scientific foundation for informing health care providers about how to provide the appropriate pain management, while minimizing the risks of opioid abuse and addiction. Topics covered include the neurobiology of opioids, the epidemiology of opioid addiction and pain, the genetic intersections of pain and addiction, and a look at the future of pain management.

NIH Pain Consortium

Patricia A. Grady, Ph.D., R.N., F.A.A.N.
Director
National Institute of Nursing Research 


The NIH Pain Consortium provides leadership for trans-NIH research activities through the identification of key opportunities in pain research and by an increase in the visibility of pain research with stakeholders. A recent national survey revealed that 25 percent of adults experienced day-long pain in the month prior and 10 percent experienced day-long pain for a year or longer. Through the presentations and panel discussions, a wide array of experts share their insights into the complex nature of pain, its management, and its impact on our society. Investigators within NIH and across the extramural research community are making great progress in elucidating the molecular underpinnings of pain and in generating therapeutic approaches that translate into clinical practice.

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Neurobiology of Opioids

Opioid Receptors: The Basis of Pain Relief and Addiction 

Mary Jeanne Kreek, M.D.

Pain is modulated by endogenous opioid peptides, and exogenous opioids are effective analgesic agents. Many drugs of abuse act directly on or affect the endogenous opioid system. The µ-opioid receptor and related endorphins modulate many physiological functions, including the hypothalamic-pituitary-adrenal stress responsive system. In positron emission tomography studies, we have shown that the highest density of µ-opioid receptors is in the thalamus and regions of dopaminergic terminals, including the amygdala, insula, anterior cingulate, caudate, and putamen. We have also shown that the long-acting opioid methadone, used in the treatment of opiate addiction, leads to only modest (20–30 percent) occupancy, and facilitates the normalization of functions modulated by the endogenous opioid system that are disrupted during heroin use, such as stress responsivity. We use a bidirectional translational research approach to develop novel animal models to study the molecular, neurobiological, and behavioral impact of opiate and other addictions. Our longstanding hypothesis, that atypical responsivity to stress and stressors contributes to the acquisition, persistence, and relapse to opiate and cocaine addiction and alcoholism, has been confirmed. Our team identifies a common variant of the µ-opioid receptor gene, A118G, and shows that it is functional, with the resulting receptor having three times greater affinity and signal transduction when ß-endorphin is the binding ligand. We hypothesize and show that the presence of this functional variant results in basal and challenge differences in stress responsive hormones, predicts a positive outcome to the treatment of alcoholism with opioid antagonists, and is associated with alcoholism and opiate addiction.

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Opiate Analgesics: Pathways to Addiction

Christopher J. Evans, Ph.D.

Opioid drugs have high addictive potential, and the misuse of opioid painkillers has escalated alarmingly in recent years. Although opioids are effective analgesics, these drugs can be profoundly euphoric, and continued use results in neuroadaptive mechanisms that oppose the acute effects and that undoubtedly contribute to maintained drug-taking and the need for increased amounts of the drug to ensure therapeutic efficacy. We discuss compensatory neuroadaptive mechanisms and present data showing that chronic, morphine-induced hyperalgesia depends on the pain modality. There are multiple opioid alkaloid drugs available for the treatment of pain, and one goal of this presentation is to highlight the opioid drug properties and pharmacologic mechanisms that address issues of safety, reduced euphoria, and the mechanisms involved with adaptive processes. Some of these properties concern differences in intrinsic activity, receptor selectivity, and pharmacodynamics. However, basic research has now revealed a pharmacological complexity of opioid drug–receptor interactions that requires us to consider every opioid drug as potentially unique with regard to receptor signaling, trafficking, and desensitization. Opioid receptors are now viewed as components of dynamic heterogeneous protein complexes that are orchestrated by ligand interactions, providing the expanded potential for differential actions mediated via the same opioid receptor protein.

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Pain and Addiction: Can We Actually See the Relationships?

Jon-Kar Zubieta, M.D., Ph.D.

Two neurotransmitters involved with the effects of opiates and other drugs of abuse (the dopaminergic and opioid), are likely to represent a point of confluence between the neurobiologies of pain and addiction. We present a series of studies in humans, focusing on the response of these systems to sustained pain. µ-Opioid and dopamine (DA) D2 receptors are quantified at baseline and during pain in healthy subjects using external imaging techniques (i.e., positron emission tomography and selective DA D2 and µ-opioid receptor radiotracers). Data are presented on the involvement of these neurotransmitter systems in the experience of pain as well as the initial evidence of their dysregulation in chronic pain conditions. We discuss the implications of the interindividual differences in DA D2 and µ-opioid receptor availability and in the capacity to activate these neurotransmitter systems. They are discussed in the context of the contributions of sex, gonadal steroids, common genetic polymorphisms, and cognitive factors. Based on these data, variations in the function of DA and opioid systems in response to pain, a physical and emotional stressor, are proposed to underlie varying risks for the initiation of drug use and the development of addiction in the context of persistent clinical pain.

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Epidemiology of Opioid Addiction and Pain
 

Opioid Addiction in the United States: From Opium to the Internet

David F. Musto, M.D., M.A.

We briefly review the history of addiction in the United States, with an emphasis on the shifting attitudes concerning the treatment of patients with opioids.

[Slides not available]

Epidemiology of Chronic Noncancer Pain and Opioid Treatment

Mark Sullivan, M.D., Ph.D.

Pain intensity and associated distress in patients with nonmalignant pain is at least as high as in patients with cancer pain. A recent World Health Organization survey of primary care patients in 15 countries reported that 22 percent of patients had pain for at least 6 months that required medical attention or interfered significantly with their daily activities. The vast majority of these patients have pain that is not proportional to objective disease, such as back pain and headache. Yet 13 percent of headache patients and 18 percent of back pain patients in the United States report that they have been unable to work full time because of their pain. Between 1980 and 2000, the rate of opioid prescribing at U.S. outpatient visits for chronic musculoskeletal pain doubled, from 8 to 16 percent of visits. In 2001, approximately 3 percent of the general population was prescribed an opioid that they used regularly for at least 1 month. In models adjusted for demographic and clinical variables, persons with depressive and anxiety disorders (OR = 2.0) or problem drug use (OR = 3.0) in 1998 were more likely to report the regular use of prescribed opioids in 2001. These patients are precisely those who have been excluded as high risk for randomized trials of opioid efficacy.

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History of Malignant Pain Treatment With Opioids

Kathleen M. Foley, M.D.

One-third of cancer patients in active therapy and two-thirds of patients with advanced disease, both adults and children, report pain that requires opioid analgesic therapy. National and international epidemiologic studies describe this consistent prevalence of cancer pain in both resource-rich and resource-poor countries.

Over the past 35 years, there has been a dramatic increase in the use of opioids for cancer pain patients based on the principle that opioid therapy is the first-line pharmacologic approach. The World Health Organization has championed the need for cancer pain relief and morphine as an essential drug in its palliative care initiatives, national cancer control programs, and more recently, in national AIDS strategies.

The chronic use of opioids in cancer patients has challenged the traditional views of opioid therapy for chronic pain. It has demonstrated that physical dependence is not a clinical issue for cancer patients. There is no limit to tolerance; opioid rotation can maximize analgesia and minimize side effects; and patients rapidly taper and discontinue use when their pain is effectively treated by specific cancer therapies. Drug misuse and abuse is rare, and two studies from India and the United States have demonstrated that the increased availability of opioids for a cancer population was not associated with prescription drug abuse.

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Epidemiology of Prescription Opioid Abuse in Young Women: Relationship to Pain

Carol J. Boyd, Ph.D., M.S.N., R.N.

According to the 2005 National Survey on Drug Use and Health (NSDUH), approximately 7 percent of adolescents (7.4 percent girls and 6.3 percent boys) and 12 percent of young adults (11.3 percent women and 13.5 percent men) have engaged in the nonmedical use of prescription pain medications (NMUPD). The motivations of NMUPD vary; however, some motivations (but not all) are correlated with attendant substance abuse problems. Indeed, based on endorsed motivations, there appear to be two groups of nonprescription medication abusers—those characterized as “self-treatment” and the other characterized as “at risk.” The number of motives is associated with the number of potential substance abuse problems (positive DAST-10 scores) and, as the number of motives increase, so too does the likelihood of a positive DAST-10 score. In addition, the more motives endorsed, the greater the likelihood of concomitant marijuana and alcohol abuse. In NSDUH and more regional samples, most abusers get their drugs from a family member or friend, usually for free. Approximately 10 percent divert their parents’ medications. A higher percentage of women give away their prescription medications and are more likely to do so to same-sex friends. Further work is needed to establish whether the "friendly sharing" among family and friends poses a risk for developing substance abuse problems.

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Genetic Intersections of Pain and Addiction

Genetic Factors in the Transition From Acute Injury to Chronic Impairment

Ze’ev Seltzer, D.M.D.

Chronic pain is a major unsolved medical, economical, and societal problem because it is so common (affecting 1 of ~3–4 adults worldwide) and because current treatments provide only partial relief that is traded off by side-effects. New treatments are needed. We describe how it is now possible to use genetic approaches to identify targets for the development of the next generation of pain killers and to revolutionize pain medicine. The rapid implementation of genetics in pain research can proceed because (1) clinically relevant definitions of pain phenotypes for genetic research are already well characterized; (2) robust statistical and epidemiological tools are “at hand”; (3) immortalization methods of human DNA, as well as the whole-genome amplification of DNA samples extracted from saliva or blood, are available, ensuring us a continuous supply of this resource on demand; and (4) massive genotyping using microarrays on chips is also possible and will soon be more economically feasible, enabling us to undertake dense, genome-wide mapping of genetic variations and gene validation. To facilitate this implementation, the number of genetic pain research teams must rapidly increase, and adequate financial support should be allocated now. When identified, the mechanisms by which these genes cause pain chronicity will be studied. A vast body of knowledge already exists, describing a plethora of neural mechanisms that have evolved to ensure a transition from acute injury to chronic impairment, including the persistence of pain. We review these mechanisms in the context of avenues for genetic research.

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Balancing Pain Relief and Risk for Addiction

Aberrant Drug-Taking Behaviors During Pain Management—What Do We Know?

Steven D. Passik, Ph.D.

Clinicians who use opioid analgesics to treat people with chronic pain must monitor outcomes in four domains. Monitoring the so-called 4 A’s (analgesia, activities of daily living, adverse effects, and aberrant drug-taking behaviors) is a way of codifying the success or failure of an opioid trial. No domain is more complex to assess and interpret than that of aberrant drug-taking. The more obvious behaviors, from the point of view of addiction or diversion, are often opaque and are certainly not routinely elicited in self-report. The less obvious behaviors are more common but ambiguous. Driven by multiple influences, these nonadherent behaviors are common; they may map on addiction or may represent several other alternatives. Emerging research suggests that aberrant behavior does map on addiction if it is repetitive or frequent, that it can be predicted by a range of new screening tools, and that it can be managed even in the highest risk patients. We present these various points and suggest risk management approaches based on these emerging data.

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Safe and Effective Opioid Prescribing in the Internet Age

Nathaniel P. Katz, M.D., M.S.

We briefly cover the epidemiology of pain and prescription opioid abuse, focusing on the connections between opioid prescribing and the abuse problem as the 21st century Internet era emerges. The role of the Internet and related technologies in the prescription opioid abuse problem is highlighted. Although the problem of pain and opioid abuse is by now well known, there have been few clear calls regarding how the problem can be comprehensively addressed. In particular, physicians, particularly primary care physicians, have been left with obligations to both relieve pain and prevent abuse but have little guidance on how to navigate these “rocky waters.” We present a simple and pragmatic approach to safe opioid prescribing for physicians that take advantage of 21st century technology.

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Treatment Development: Hope of the Horizon

Bivalent δ-µ Opioid Ligands: Potential for Pain Control Without Tolerance or Dependence

David J. Daniels, M.D., Ph.D.

The relationship between morphine-induced tolerance and dependence, and pharmacological interaction between δ- and µ-opioid receptors has been observed for more than 20 years. Studies have revealed that morphine-induced tolerance and dependence can be reduced without compromising analgesic activity by antagonizing the δ-opioid receptor. Because it has not yet been determined whether this is a consequence of the direct association between δ- and µ-opioid receptors, or due to functional modulation involving neuronal circuitry, we have designed bivalent opioid ligands that contain µ-agonist and δ-antagonist pharmacophores to address this issue. Bivalent ligands with the shorter spacers produced both tolerance and dependence similar to both morphine and control monovalent ligands on chronic administration to mice. However, when the distance between the two pharmacophores of the bivalent ligand exceeded 18 atoms, the compounds no longer produced tolerance or dependence. These data suggest that physical interaction between the d- and µ-opioid receptors modulates µ-mediated tolerance and dependence. Additionally, one of these compounds was found to be 50-fold more potent than morphine by intravenous administration, suggesting a previously uncharacterized approach for the development of analgesics, devoid of tolerance or dependence.

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New Opioid Formulations: Hope on the Horizon

Pamela P. Palmer, M.D., Ph.D.

Although there are many complex issues to discuss regarding the use and abuse of opioids, three major areas of concentrated effort should have a direct impact over the next decade on the overall safety of prescribing and using opioids to treat acute and chronic pain. First, there are new abuse-resistant formulations of opioids. We present key aspects of opioid formulations that resist abuse, including safer extended-release formulations. We also highlight the importance of high-bioavailable opioid formulations. Second, we discuss the safer dispensing of opioids, including novel drug-device products in development for the safer dosing of analgesics in both the inpatient and outpatient setting. Third, we report on efforts at mitigating dose escalation by developing opioid formulations with less tolerance development. Clinical aspects of opioid tolerance development, and key molecular targets for novel therapies to deter opioid tolerance are covered.

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Real-Time fMRI: A New Method for Controlling Targeted Brain Activation Through Training, With Application to Pain Control and Addiction

R. Christopher deCharms, Ph.D.

It is now possible to visualize brain activation in real time using real-time functional magnetic resonance imaging (rtfMRI). This may allow patients to observe and learn to control the brain mechanisms underlying their own disease processes. Pain regulation is mediated through a powerful and highly developed endogenous modulatory system spanning multiple brain regions. Bringing this system under conscious control could provide a novel mechanism to decrease pain, using rtfMRI training.

In experiments designed to test this hypothesis, we provided healthy experimental subjects and chronic pain patients with rtfMRI information from the regions associated with pain perception and pain control, including the rostral anterior cingulate cortex (rACC). When subjects deliberately induced increased versus decreased rACC activation, there were corresponding changes in the perceived pain intensity caused by an applied noxious thermal stimulus or ongoing chronic pain. This was not observed in four independent control groups that received training without rtfMRI. Thus, it is possible that subjects may learn explicit control over brain activation using rtfMRI-based training, with a concomitant impact on cognitive processes. This procedure is being actively investigated in ongoing clinical trials on chronic pain and addiction.

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Concluding Remarks

Integrating Neuroscience and Clinical Practice To Better Address the Complex Needs of Pain Patients at Risk for Addiction

Howard L. Fields, M.D., Ph.D.

We provide a summary and overview of the major issues raised in the meeting and addresses such issues as the neurobiology of opioid actions and the process of how they relate to the real-world problems of patient care. The risks and benefits of opioid use are placed in a clinical perspective, covering pain management and the challenges of tolerance, dependence, and addiction.

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