Monday, December 4, 2006 Panel Session Co-Morbid Pain
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Neuropsychopharmacology (2006) 31, S1-S69 © 2006 Nature Publishing Group All rights reserved 0893-133X/06 www.neuropsychopharmacology.org S1 Monday, December 4, 2006 sented on the involvement of these neurotransmitter systems in re- sponses to sustained pain, a physical and emotional stressor, and their Panel Session dysregulation in chronic pain conditions. In addition, we will discuss Co-Morbid Pain and Addiction: Novel Treatments the psychophysical implications of inter-individual differences in DA D2 and µ-opioid receptor availability and in the capacity to activate these neurotransmitter systems. These will be discussed in the con- Clinically Significant Advances in Understanding Opiate text of the contribution of sex, gonadal steroids, common genetic Receptors polymorphisms and cognitive factors to these individual variations. Gavril W. Pasternak* Regarding the latter, we will discuss recent and new data on the ef- fects of expectation of relief on the function of these neurotransmit- Molecular Pharmacology, Memorial-Sloan Kettering, New York, tersystems and associated neuronal circuits and their contribution to NY, USA individual differences in placebo responding. Examination of these Opiates are widely used in the treatment of pain. Clinicians have long cognitively-modulated, resiliency mechanisms further provides a recognized the need to individualize therapy based upon the widely novel avenue for the development of treatment strategies and the un- varying responses of individual patients. However, the reasons for derstanding of treatment non response in various neuropsychiatric this have remained obscure. Most of the opiates used clinically are se- conditions. lective for mu, or morphine-preferring, receptors, raising the ques- tion why the disparities in response among patients can be so great. Functional Neuro-Imaging of Chronic Pain and Opiate Response Another question among clinicians involves the use of Opioid Rota- David Borsook* tion, in which patients highly tolerant to one opioid can be switched to another with a marked increase in analgesic effectiveness. The Psychiatry, McLean Hospital, Belmont, MA, USA utility of this approach appears to rest upon the development of in- Opioids are one major class of drugs used in the treatment of chronic complete cross tolerance among opioids, in which the relative po- pain. Currently there is great concern about the use of opioids in the tency of one drug to another changes in tolerant compared to naïve treatment of non-malignant chronic pain at a patient level (opioid patients. These clinical observations can be replicated in a variety of phobia), clinical/provider level (physicians being reluctant to pre- animal models. Perhaps the most dramatic example is the CXBK scribe because of Drug Enforcement Agency (DEA)), related rules or mouse, which is insensitive to morphine, but retains full sensitivity to scrutiny and a societal level (opioid addiction is costly). Over the past other mu opioids, including heroin, methadone and fentanyl. One 5 years opioid prescription drug abuse has evolved into a national possible explanation for these observations involves multiple sub- epidemic. Chronic pain treatment with opioids is a clinically unusual types of mu receptors, a concept first proposed over 25 years ago. Ini- pharmacotherapy in the sense that we administer a drug class that is tial work utilized traditional pharmacological approaches, including known to have addictive properties, and furthermore, do this on a detailed binding studies and novel antagonists capable of selectively long-term basis. This situation raises a number of important ques- blocking some mu actions and not others. However, the cloning of tions including: (1) Are chronic pain patients more prone to becom- the mu opioid receptor MOR-1 has opened new insights into the ac- ing addicted to drugs of abuse? Chronic pain is known to produce a tions of these drugs. MOR-1 encodes a traditional 7 transmembrane number of changes in central nervous systems (e.g., chronic stress) G-protein coupled receptor. To date, over 20 splice variants of MOR- alterations in neural circuitry such as loss of neurons in frontal lobe 1 have been reported in mice and almost a dozen in humans. All the and thalamus that could affect susceptibility to addiction. In addi- full length variants display the anticipated selectivity and affinity for tion, these patients are at greater risk simply through sustained access mu opioids, which is not surprising since the seven transmembrane to prescription drugs and because the opioids commonly prescribed domains are all identical within each species. Their differences are re- for chronic pain such as oxycontin and hydrocodone seem to have a stricted to the tip of the intracellular C-terminus. However, these higher level of abuse, or are considered more “attractive”. (2) Why variants differ in their localizations within the CNS and within the don’t all chronic pain patients receiving chronic opioids become ad- cell and can be distinguished from each other functionally as well. dicted? Is there something special about the changes in neural cir- These studies illustrate the complexity of the mu opioid system. It cuitry in chronic pain that protects many patients against addiction will be interesting to see if these variants may lead to differences in despite prolonged use? Links between opioid addiction and chronic opioid actions other than analgesia, including reward and addictive pain may be considered at a number of levels including: (1) each on potential. Although they cannot yet be used to predict the optimal its own produces alteration in brain function; (2) each condition agent for a specific patient, they provide insights into why we must (chronic pain or addiction) may independently result in alteration in continue to individualize therapy. reward function; and (3) chronic opioid use, even without pain can produce significant changes in the response to acute pain and clinical pain as observed in methadone maintenance patients. The segrega- Endogenous Opioids and Dopamine in the Response to Pain in tion in the approach to chronic opioid use or abuse is very different Humans amongst the two main clinical groups who see these patients: pain Jon-Kar Zubieta* and addiction specialists. As a result of differences in clinical practice Psychiatry & Radiology, Univ of Michigan, Ann Arbor, MI, USA approaches by pain clinicians and addiction specialists, numerous pa- tients fall between the cracks. In this presentation we will present This presentation will focus on the function of two neurotransmitter new data on the use of functional magnetic resonance imaging systems, the endogenous opioid and dopaminergic (DA), implicated (fMRI) in two domains: (a) the role of reward circuitry in acute and in response to pain in human subjects, as well as in the effects of opi- chronic pain and (b) the ability to evaluate the effects of opioids on ates and other drugs of abuse. Mu-opioid and DA D2 receptors were CNS function in human and animal models. The insights gained quantified at baseline and during pain in healthy subjects using exter- from these approaches indicate that fMRI may provide an objective nal imagining techniques (positron emission tomography and selec- measure of alterations in neural circuits that may differentiate “ad- tive DA D2 and µ-opioid receptor radiotraces). New data will be pre- dicted” brain circuits from “non-addicted” brain circuits in patients ACNP 2006 Annual Meeting S2 with chronic pain and provide a method for validation of tools used smoking at least five years before illness onset than in controls. to monitor patients in the clinic. Thus, schizophrenia vulnerability may be associated with in- creased vulnerability to starting smoking. People from the general population are not good controls in schizophrenia studies unless a Answering the Key Questions About Co-Morbid Pain and Addiction: careful control of educational levels and gender is performed. After Intersection of Clinical Research, Epidemiology, and Policy gender stratification, patients with other severe mental illnesses Nathaniel Katz* may be a better control group since they are similar to schizophre- Anesthesia, Tufts Univ. School of Medicine, Boston, MA, USA nia patients in socioeconomic and educational backgrounds and share other confounding factors such as increased alcohol and ille- This enormous gap between vigorous laboratory research and scant gal drug use and treatment settings. When combining 18 studies clinical research on pain and opioid abuse is beginning to close. (from 9 nations), the significant world average OR for current There has been a rapid acceleration of clinical research in the areas of smoking in schizophrenia versus other mental illnesses was 1.9. epidemiology, patient assessment, pharmaceutics, and clinical inter- Three studies used logistic regression to control for confounding ventions. Several survey studies on patients in opioid abuse treat- factors, providing significant adjusted ORs ranging between 2 and ment have found the prevalence of co-morbid chronic pain ranging 3. Limited tobacco access can eliminate the strong association be- from 25-62%. In pain treatment settings, prevalence of urine toxicol- tween schizophrenia and current smoking in some nations. Of the ogy screens suggestive of co-morbid substance abuse has been found 5nonsignificant ORs from 42 OR, three came from Colombian to range from 20-40%. An important point beginning to be illumi- studies comparing