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Highlights from Pain, Opioids, and Addiction: An Urgent Problem for Doctors and Patients

 
Frederick W. Burgess, MD, PhD

Medscape Neurology & Neurosurgery.  2007; 2007 Medscape

Posted 04/27/2007

Introduction

On March 5-6, 2007, the National Institute on Drug Abuse (NIDA) and the American Medical Association sponsored a joint meeting at the NIDA campus in Bethesda, to present information on opioid prescribing, chronic pain, and the increase in prescription drug abuse. (See the agenda at: http://conferences.masimax.com/opioid/agenda.cfm.)

The program was divided into 5 educational sessions featuring presentations by NIDA grant recipients and other experts in pain treatment and addiction medicine, followed by a commentary and panel discussion. The sections were Neurobiology of Opioids, Epidemiology of Opioid Addiction and Pain, Genetic Intersection of Pain and Addiction, Balancing Pain Relief, Risk for Addiction, and Treatment Development: Hope on the Horizon.

Overall, the discussions were extremely well balanced, demonstrating clear support and recognition of the value of opioid therapy for cancer and chronic noncancer pain conditions. Presentations by Dr. Kathleen Foley[1] of the Memorial Sloan Kettering Cancer Center and Dr. Nathaniel Katz[2] of Tufts University, served to highlight the great strides that have been made in the treatment of cancer pain and chronic pain. Both physicians cited the difficulty encountered by physicians caring for pain patients in trying to provide compassionate care to the patient in need of opioid analgesics, and the concern for the social and legal ramifications of prescription drug diversion. The value of opioid therapy in acute traumatic pain and for cancer pain is no longer controversial, although some improvement is still needed. Chronic opioid therapy for chronic pain conditions continues to be surrounded by considerable controversy. This in part stems from a lack of well-controlled clinical trials of sufficient duration (years), because much of the data available is of only intermediate duration. Furthermore, the high incidence of mental health disorders and substance misuse among chronic pain populations has created much concern. Coupled with the rising death rate attributed to accidental prescription drug overdose, there is a need for a closer look at the links between pain and addiction.[3]

Genetics of Pain, Substance Abuse, and Addiction

Much of the basic science data presented by the investigators indicated a substantial basis for a genetic contribution to substance abuse and addiction liability, and possibly a genetic predisposition to specific pain syndromes. However, the tendency to manifest addiction and/or pain is multifactorial and is unlikely to be explained by a single gene. Various factors play into the manifestation of addiction and pain, including social environment, the impact of the abused drug on brain adaptation, the impact of injury or pain on the nervous system, and genetic predisposition.

In the section on the Neurobiology of Opioids, Dr. Mary Jeanne Kreek of Rockefeller University discussed the interplay between opioid receptors, alterations in the release and regulation of stress response mediators, and genetic polymorphisms that contribute to substance abuse.[4] Recent studies on single nucleotide polymorphisms have demonstrated an enhanced response of the A118G micro-opioid receptors (MOR) variant to endogenous opioid agonists, which appears to be associated with an increased tendency for alcohol abuse.[5,6] Alcohol abusing subjects with this common variant appear to respond well to naltrexone therapy in maintaining their abstinence from alcohol, supporting a common thread between various substance abuse conditions. Furthermore, this variant is associated with an altered stress response pattern, which may contribute to relapse into substance abuse.

MOR receptors appear to show a variety of polymorphic features, which are likely to play an important role in ligand binding and signal transduction with various opioid agonists. Furthermore, specific opioid agonists appear to display differential effects upon binding with the receptor. The more potent opioid agonists, such as fentanyl and methadone, trigger internalization of MOR receptors.[7,8] The MOR receptors are subsequently processed via lysosomes and recycled into the membrane, thereby restoring efficacy. Weaker opioid agonists or partial agonists, such as morphine, do not trigger internalization, and may play a role in the development of tolerance. Thus, the development of tolerance, dependence, and analgesia are subject to an interplay of many variables, making predictions for a given individual difficult at best. Basic science studies in the MOR knockout mice support a significant interplay between the MOR receptor and the reward response to morphine, marijuana, and alcohol, which is absent in the knockout strain.

Data presented by Dr. Ze'ev Selzer on the genetics of pain in various cross strains of the rat and mouse suggested that genetic links to the development of various pain syndromes can be demonstrated, but that they are syndrome specific and may be found scattered throughout the genome.[9] He suggests that scientists will be able to map most of these by 2010, provided that adequate funding is available for pain research. An example of the value in the identification of genetic determinants for several pain syndromes, such as persistent lumbar radiculopathy following lumbar diskectomy, can rely on screening and mapping in animal models and then be applied to patients. Preliminary studies in rat/mouse models identified a target genetic polymorphism in the expression of GTP cyclohydrolase and tetrahydrobiopterin contributing to the development of lumbar radiculopathic pain, and corroborated these findings in human patients.[10] Another genetic polymorphism involving catechol-O-methyl-transferase variants (Val158Met) and the MOR A118G, has been found to affect the analgesic effects of opioid therapy in cancer pain patients.[11] Patients with the OPRM1 AA and COMT Met/Met genotypes required 93% less morphine than those with the COMT Val/Val and OPRM1 GG genotype.[11] Results from these comparative studies may help the identification of new targets for drug therapy, or the ability to select the most appropriate opioid for the individual patient to obtain the best result.

Nicotine Abuse

One common thread noted throughout the conference is the high incidence of nicotine abuse among addicts, and a similar prevalence of tobacco abuse among chronic pain patients. Dr. Steven Passik of the Memorial Sloan Kettering Cancer Center cited tobacco abuse as a risk factor to predict drug abuse/misuse among pain clinic populations, and explained that it may be a further manifestation of a susceptibility to addiction liability and opioid abuse.[12,13] It is estimated that pain patients exhibit a tobacco abuse pattern 3 times that of the general population. Factors such as smoking, a history of prior substance abuse, and coexisting mental health disorders should be considered as potential risk factors for prescription opioid misuse, and should be carefully monitored, even in the absence of obvious aberrant behavior.

Functional and Binding Characteristics of Opioid Receptors and the Interaction Between Receptor Subtypes

Another interesting topic discussed by several investigators, was the impact of post-translational changes on the functional and binding characteristics of the various opioid receptors, and the interaction between receptor subtypes. Membrane receptors, such as the MOR and delta-opioid receptor (DOR), appear to form heteromeric dimers, and in some settings large oligomeric associations, thereby influencing the response to activation by agonists. There is also evidence of dimeric linkages forming between MOR and alpha-2a adrenergic receptors. Coactivation of the MOR/DOR dimer by agonists produces analgesia; however, the DOR receptor co-activation appears to accelerate the production of tolerance and dependence. Data presented by David J. Daniels, MD, PhD, examined the role of bivalent DOR-MOR opioid ligands on this interaction between the two opioid receptors. Preliminary animal studies on the bivalent ligands suggest that synthesizing a potent mu agonist linked by a spacer of specific length to a DOR antagonist induces potent analgesia without the development of tolerance or withdrawal phenomenon in animal models.[14] This particular class of compounds is still in early phase testing and is not yet available for human clinical trials, but it provides interesting insight into the interaction between the different receptor subtypes. The potential applications for an opioid agonist with little risk of tolerance would be a remarkably useful addition to pain treatment.

Substance Abuse and Addiction

Several speakers focused on recent developments in our understanding of substance abuse and addiction. Recent improvements in pain treatment, marked by the aggressive prescribing or potent opioid analgesics for cancer and chronic pain, has been notably followed by a dramatic increase in prescription opioid misuse in communities previously spared from illegal drug abuse over the past 10 years. Perhaps most alarming has been the increasing prevalence of drug misuse among children and young adults under the age of 25. Dr. Carol Boyd presented data on this trend in young women.[15,16] Several interesting findings from her research indicate that young women appear to glean much knowledge pertaining to the use of opioid medication from the internet. They exhibit considerable sophistication in their understanding of the medications and how to use them. The majority of opioid misuse in this population appears to be centered on the self-treatment of pain in themselves, or in others, as opposed to abusing the medication to obtain a 'high.' Most young women appear to access prescription opioids from their friends and relatives, with prescriptions obtained directly from physicians accounting for a smaller percentage. Among individuals seeking opioid medication strictly for the purpose of abuse, 'dealers' accounted for a more significant source among young men; however, young women continued to report friends and family as their primary source. Internet access to medication was a very small percentage (< 2%) as a source of misused opioids among the young adult population. However, users seeking opioid medication with the intention of abuse were more likely to try to obtain prescription opioids via the internet.

Prevalence of Chronic Pain

Dr. Mark Sullivan, from the University of Washington, presented data on the prevalence of chronic pain citing data from a World Health Organization survey, which showed a world-wide prevalence of chronic pain in the range of 20% to 30%.[17] Fairly consistent was the finding that women are afflicted nearly twice as often as men. Low back pain, headache, and joint pain are the most common problems. In a study performed by Dr. Sullivan and colleagues that was reported in 2006, it was shown that problem drug use was significantly associated with co-existing mental health disorders and a history of prior substance abuse.[18] However, problem alcohol use did not appear to be associated with problem opioid use. It was suggested that mental health disorders may predispose patients to seek opioid therapy, in part to control their psychological symptoms and their coexisting pain problem. Physical pain and mental pain may share the same neural substrates, thus considerable overlap is not surprising. This draws attention to the need to seek and address mental health issues in patients presenting with chronic pain, before proceeding with opioid therapy.

New Opioid Dose Forms

The need for the development of new opioid dose forms was presented by Dr. Pamela Palmer, from UCSF.[19] She cited that many of the difficulties with current opioid preparations relates to their short duration of action, and the need for multiple doses or slow-release formulations to sustain analgesia. Current sustained-release preparations, such as the transdermal patch and slow release tablets, are prone to tampering and misuse.[19] Presently available transdermal administration devices frequently leave a substantial amount of unused medication in the package, which must be carefully discarded to prevent diversion of the remaining content. A number of new opioid formulations are in development to reduce tampering through novel physical and chemical structures, or through the combination of opioid antagonists that will block the drug effect if it is improperly administered.

Measurement of Pain

One of the greatest difficulties in treating patients with pain is the highly subjective nature of the pain sensation. The measurement of pain intensity is primarily dependent on the patient's report, often with little physical evidence to provide objective corroboration. Even in circumstances where there is objective evidence of anatomic abnormality, population studies would suggest that radiographic findings are often confusing, as many subjects may display similar findings, without pain. Recently, the use of functional magnetic resonance imaging (fMRI) has provided some hope that pain may be more objectively assessed via direct imaging of the neural patterns observed through this technology. Dr. R. Christopher deCharms of Omneuron, Inc., presented data showing the impact of real-time fMRI imaging in the treatment of pain patients.[20] Through a series of training sessions, pain patients monitoring their own brain fMRI activity were capable of controlling their pain using relaxation techniques. Currently, this technology is quite expensive, but with further technological developments, fMRI may provide guidance in assessing various treatments using objective criteria to supplement the subjective report of the patient.

Conclusion

Great strides have been made in both our understanding and treatment of addiction and pain over the past 30 years. Despite these advances, substance abuse continues to be a major problem, recently fueled by the diversion and misuse of prescription opioid medications. Opioids remain our most effective means to control pain, and their appropriate use is an essential cornerstone to the practice of medicine. However, careful and considered prescribing of opioid medications must be adopted by all physicians to prevent inappropriate misuse and diversion. Improvements in our understanding of individual genetic predispositions to pain, addiction, and responsivity to opioid medication will help guide clinicians in applying the most effective treatment in the near future.

Supported by an independent educational grant from Cephalon.

References

  1. Foley KM. Advances in cancer pain management in 2005. Gynecol Oncol. 2005;99:S126.
  2. Katz NP, Adams EH, Benneyan JC et al. Foundations of opioid risk management. Clin J Pain. 2007;23:103-118. Abstract
  3. NIDA InfoFacts: Prescription Pain and Other Medications. Available at: http://www.nida.nih.gov/infofacts/PainMed.html Accessed April 20, 2007.
  4. Kreek MJ. Methadone-related opioid agonist pharmacotherapy for heroin addiction: history, recent molecular and neurochemical research and future in mainstream medicine. Ann NY Acad Sci. 2000;909:186-216. Abstract
  5. Bart G, Kreek MJ, Ott J, et al. Increased attributable risk related to a functional mu-opioid receptor gene polymorphism in association with alcohol dependence in central Sweden. Neuropsychopharmacology. 2005;30:417-422. Abstract
  6. Nishizawa D, Han W, Hasegawa J, et al. Association of micro-opioid receptor gene polymorphism A118G with alcohol dependence in a Japanese population. Neuropsychobiology. 2006;53:137-141. Abstract
  7. Keith DE, Murray SR, Zaki PA, et al. Morphine activates opioid receptors without causing their rapid internalization. J Biol Chem. 1996;271:19021-19024. Abstract
  8. Hashimoto T, Saito Y, Yamada K, et al. Enhancement of morphine analgesic effect with induction of mu-opioid receptor endocytosis in rats. Anesthesiology. 2006;105:574-580. Abstract
  9. Seltzer Z, Dorfman R. Identifying genetic and environmental risk factors for chronic orofacial pain syndromes: human models. J Orofac Pain. 2004;18:311-317. Abstract
  10. Tegeder I, Costigan M, Griffin RS, et al. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med. 2006;12:1269-1277. Abstract
  11. Reyes-Gibby C, Shete S, Rakvag T, et al. Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene. Pain. 2006 Dec 5; [Epub ahead of print]
  12. Friedman R. Li V, Mehrotra D. Treating pain patients at risk: evaluation of a screening tool in opioid-treated pain patients with and without addiction. Pain Med. 2003;4:182-185. Abstract
  13. Passik S, Kirsh K, Whitcomb L, Portenoy RK, Katz NP, Kleinman L, Dodd SL, Schein JR. A new tool to assess and document pain outcomes in chronic pain patients receiving opioid therapy. Clin Ther. 2004;26:552-561. Abstract
  14. Daniels D, Lenard N, Etienne C, et al. Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series. PNAS. 2005;102:19208-19213. Abstract
  15. Boyd C, McCabe S, Cranford J, et al. Prescription drug abuse and diversion among adolescents in a southeast Michigan school district. Arch Pediatr Adolesc Med. 2007;161:276-281. Abstract
  16. Teter C, McCabe S, LaGrange K, et al. Illicit use of specific prescription stimulants among college students: prevalence, motives, and routes of administration. Pharmacotherapy. 2006;26:1501-1510. Abstract
  17. Gureje O, Von Korff M, Simon GE, Gater R. Persistent pain and well being: a World Health Organization Study in Primary Care. JAMA. 1998;280:147-151. Abstract
  18. Sullivan M, Edlund M, Zhang L, et al. Association between mental health disorders, problem drug use, and regular prescription opioid use. Arch Intern Med. 2006;166:2087-2093. Abstract
  19. Fudala PA, Johnson RD. Development of opioid formulations with limited diversion and abuse potential. Drug Alcohol Depend. 2006;83:S40-S47. Abstract
  20. deCharms R, Maeda A, Glover G, et al. Control over brain activation and pain learned by using real-time functional MRI. PNAS. 2005;102:18626-18631. Abstract

 
Frederick W. Burgess, MD, PhD, Clinical Associate Professor of Surgery (Anesthesiology), Brown University, The Warren Alpert Medical School, Providence, Rhode Island; Attending Anesthesiologist, Rhode Island Hospital, Providence, Rhode Island

 
Disclosure: Frederick W. Burgess, MD, PhD, has disclosed no relevant financial relationships.

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Highlights from Pain, Opioids, and Addiction: An Urgent Problem for Doctors and Patients

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