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Problem Patient or Problem Prescription?

Problem Patient or Problem Prescription?. Ken Roy, MD Tulane Department of Psychiatry Addiction Recovery Resources of New Orleans 504-780-2766 www.arrno.org. Scope. Problem patients Problem prescriptions Classes of addicting drugs Recognition of addiction

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Problem Patient or Problem Prescription?

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  1. Problem Patient or Problem Prescription? Ken Roy, MD Tulane Department of Psychiatry Addiction Recovery Resources of New Orleans 504-780-2766 www.arrno.org

  2. Scope • Problem patients • Problem prescriptions • Classes of addicting drugs • Recognition of addiction • What to do about problem patients

  3. Potential Problem Patients • Family history of alcoholism • External locus of control • Pain persistent or out of proportion • Litigation • Multiple meds

  4. Problem Prescriptions • Soma, Fiorinal, Valium, Xanax • Ritalin, Adderall • Vicodin, Percodan, Ultram, OxyContin

  5. Classes of Addicting Drugs • Related to the reinforcing pathway • Three main classes • Sedative hypnotics and opioids contain the vast majority of problem prescriptions

  6. Sedative Hypnotics • Active in the GABA system • Alcohol • Benzodiazepines (Rohypnol) • Barbiturates (Fiorinal) • Anxiolytics & Hypnotics (Ambien, Soma, Sonata)

  7. Opiates • Active in the endorphin systems • Vicodin, other oxy & hydro codones • Especially ES formulations & OxyContin • Ultram • Methadone

  8. Stimulants • Active in the dopamine system • Amphetamines (Adderall) • Others (Ritalin, Cylert) • *Decongestants

  9. The Case AgainstChronic Sedative Hypnotics • Short term anxiolytic in non-recovering patients • No controversy • Effects on the GABA system • Effects on mood, anxiety and insomnia • Alternatives

  10. The GABA System • Cause tolerance (40,42,43) • Down regulate receptors (36,37,38) • And receptor function (39,40) • Decrease effect of endogenous anxiolytics (41) • Cause physical dependence (59)

  11. Mood, Anxiety and Insomnia • Paradoxical anxiety with long term use (45) • Cause depression (54,55,56,57) • Not effective long term for sleep (44) • Make opiates less effective (58) • No evidence of long term efficacy for PTSD (60)

  12. Alternatives to Sedative Hypnotics (Benzo’s) • SSRI’s and TCA’s • Better for GAD (46,47,48,49) • Better for panic (49,50,51,52) • Better for agoraphobia (53) • Better for “stress” (61) • Quetiapine, Trazodone, Doxepin, etc.

  13. The Case Against Chronic Opiates in Chronic Pain • Acute vs. chronic pain • The effects on the endogenous opiate system • The effects on the perception of pain • The effects on activity and behavior • Alternatives to chronic opiate analgesia

  14. Acute vs.Chronic Pain • Acute - perioperative, traumatic, infectious • No controversy (except monitoring for relapse) • Chronic • Malignant or progressive • No controversy • Non malignant • Huge controversy (1)

  15. Chronic Non-Malignant Pain • Subjective pain relief • Few studies • Urban - 5 patients (2) • Taub & Tennant - both anecdotal (3,4) • Portnoy - reduced perception of pain in 1/3 (5) • Improvement in function • Not demonstrated (1,6)

  16. It Doesn’t Work • “Overall, the use of opioids in chronic pain of non malignant origin will achieve analgesic benefit in some patients, while improved function has not yet been adequately demonstrated.”(1) • “Until opioid therapy can be shown to yield long term outcomes that are superior, we cannot endorse it as a treatment of choice for chronic non cancer pain.” (7)

  17. Even in Non Addicts • “In patients with treatment resistant chronic regional pain of soft tissue or musculoskeletal origin, nine weeks of oral morphine in doses of up to 120 mg daily may confer analgesic benefit with a low risk of addiction, but is unlikely to yield psychological or functional benefit.” (6)

  18. The Endogenous Opiate System • Tolerance • B-Endorphin neurons become tolerant after chronic morphine administration (8) • Release of Pro-opiomelanocortin-derived peptides decreased in tolerance (9) • Pro-opiomelanocortin synthesis and B-Endorphin utilization down-regulated in morphine tolerance (10,11)

  19. The Perception of Pain • Chronic opiates cause sensitization • Hyperalgesia caused by noxious stimulation is similar to hyperalgesia caused by chronic opiates (15) • Thermal hyperalgesia develops in morphine tolerance (16)

  20. Activity and Behavior • Depression • Opiates and opiate system implicated in model of learned helplessness (17,18) • Opiates cause depression (19,20) • Potential for relapse • Opiate use increases potential for relapse (21,22,23)

  21. Alternatives • Multidisciplinary chronic pain treatment programs • Nerve Blocks (24) • Psychotherapy (25,26,27,28,29) • Acupuncture (30) • Exercise (25,31,32) • Spiritual growth and recovery (33)

  22. Substance Abuse • Ubiquitous • Social problem • Legal problem • Economic Problem

  23. Criteria for Substance Abuse • Recurrent use affecting role obligations • Recurrent use where hazardous • Recurrent use causing legal problems • Recurrent use causing social or interpersonal problems

  24. Prevalence • Almost 50% of persons age 21 abuse alcohol • 70% drink • 22% of persons 18 – 22 years of age use illicit drugs • 76% are employed • Rate in college students 21%

  25. Treatment • Harm reduction strategies • Designated Driver • Education and conversation • Response to behavior • Don’t excuse behavior • Don’t remove consequences • Most people discontinue SUBSTANCE ABUSE unless they develop SUBSTANCE DEPENDENCE

  26. Criteria for Substance Dependence • A maladaptive pattern of use, causing significant impairment or distress as manifested by three (or more) of the following seven criteria, occurring at any time in the same twelve months • Tolerance, as defined by: • a need for increased amounts to achieve effect • markedly diminished effect from using the same amount

  27. Substance Dependence continued • withdrawal, as manifested by: • characteristic withdrawal syndrome • the same substance is used to avoid or relieve withdrawal symptoms • the substance is taken in larger amounts or over a longer period than was intended • there is a persistent desire or unsuccessful efforts to cut down or control use

  28. Substance Dependence continued • a great deal of time is spent in activities necessary to obtain or use the substance or recover from it’s effects • important social, occupational, or recreational activities are given up or reduced because of substance use

  29. Substance Dependence continued • the substance use is continued despite knowledge of having a persistent or recurring physical or psychological problem that is likely to have been caused or exacerbated by the substance (ulcer, depression, etc.)

  30. Incidence of Substance Dependence • 14.1% National Comorbidity Study 1994 • Other drug dependencies in 7.5% of these • 5% to 15% is the range in previous studies

  31. Substance Dependence Shorthand • Compulsion • Loss of Control • Continued use in the face of adverse consequences

  32. The Disease of Addiction • Criteria for a disease • Recognizable symptoms • Predictable Course • Common Cause

  33. The Course of Addictive Disease • Progressive • Affects all organ systems • Associated with the cause of death • A disease of relationships • Disturbance in the relationship with self and others • Based on dishonesty in the form of denial

  34. The Cause of Addictive Disease • Genetic • Experience - Family History • Family Studies • Twin Studies • Adoption Studies

  35. Importance of Disease Orientation • Cause - not Effect of Something Else • Therefore a primary illness • Helps to understand Denial • Providers don’t blame their patients • Patients Have a Healthy Target to Work on

  36. Impact on Treatment • Abstinence is the Only Reasonable Goal • Use Alters Neurotransmitters • Denial is the Primary and Universal Symptom • Preserves the Right to Drink or Use • Identification With Others Possible • OK Not to Have Coping Skills • Treatment Takes Time • Levels of Care can provide time

  37. Contribution of Environment • Similarity to TB • Impact of Using on Emotional Development

  38. Abstinence • Similarity to Diabetes • AA/NA/GA/RR not MM • Common Experiences • Fellowship • Impact on Emotional Development

  39. Getting Help • Public Sector • Overcrowded, under funded, restrictive • 32 Detox beds – 900 waiting for treatment • Private Sector • Effective, welcoming, shame reducing • Requires Parity (Non-discrimination) for maximal effectiveness • Current insurance coverage inadequate and often inappropriate

  40. So, what do I do? • Call it like you see it • Don’t shame the patient • May point out consequences • Be realistic, don’t try to “scare” the patient • Refer to appropriate addiction specific practices • JPSAC • Public • ARRNO • Private – Insurance, etc

  41. Selected Bibliography on the Use of Opioids in Addiction1.     Schug SA, Merry AF, Acland RH:Treatment principles for the use of opioids in pain of nonmalignant origin. Drugs 1991; 42 (2): 228-2392.     Urban BJ, France RD, Steinberger EK, Scott DL, Maltbie AA:Long-term use of narcotic/antidepressant medication in the management of phantom limb pain.Pain 1986; 24: 191-1963.     Taub A:Opioid analgesics in the treatment of chronic intractable pain of non-neoplastic origin. In Kitahata LM & Collins JG (Eds) Narcotic analgesics in anesthesiology, pp. 199-208, Williams & Wilkins, Baltimore, 19824.     Tennant FS, Uelman GF:Narcotic maintenance for chronic pain.Postgraduate Medicine 1983; 73: 81-945.     Portenoy RK: Chronic opioid therapy in nonmalignant pain.J Pain and Symptom Management 1990; 5: S46-626.     Moulin DE, Iezzi A, Amireh R, Sharpe WK, Boyd D, Merskey H:Randomized trial of oral morphine for chronic non-cancer pain.Lancet 1996; 347(8995): 143-77.     Schug SA, Large RG:Opoids for chronic non-cancer pain. Pain - Clinical Updates 1995; 3:3.8.     Zhang G, Lagrange AH, Ronnekleiv OK, Kelly MJ:Tolerance of hypothalamic beta-endorphin neurons to mu-opioid receptor activation after chronic morphine.J Pharmacology & Experimental Therapeutics 1996; 277(1): 551-89.     Antonio Martinez J, Vargas MI, Fuente T, Del Rio Garcia J, Milanes MV:Plasma beta-endorphin and cortisol levels in morphine tolerant rats and in naloxone-induced withdrawal.European J Pharmacology 1990; 182(1): 117-2310. Mocchetti I, Ritter A, Costa E:Down-regulation of proopiomelanocortin synthesis and beta-endorphin utilization in hypothalamus of morphine-tolerant rats.J molecular neuroscience 1989; 1(1): 33-811. Bronstein DM, Kelsey JE, Akil H:Regulation of beta-endorphin biosynthesis in the brain: different effects of morphine pelleting and repeated stress.NIDA Research Monograph 1991; 111: 113-3212. Suh HH, Tseng LF:Different types of opioid receptors mediating analgesia induced by morphine, DAMGO, DPDPE, DADLE and beta-endorphin in mice.Naunyn-Schmiedebergs Archives of Pharmacology 1990; 342(1): 67-7113. Tseng LF, Collins KA, Wang O:Differential ontogenesis of thermal and mechanical antinociception induced by morphine and beta-endorphin.European J Pharmacology 1995; 277(1): 71-614. Bronstein DM, Gutstein HB, Akil H:Effects of chronic morphine treatment on beta-endorphin-related peptides in the caudal medulla and spinal cord. J Neurochemistry 1993; 60(6): 2304-715. Rohde, DS, Detweiler DJ, Baasbaum AI: Spinal cord mechanisms of opioid tolerance and dependence: fos-like immunoreactivity expression increases in subpopulations of spinal cord neurons during withdrawal.Neuroscience 1996; 72(1): 233-24216. Mao J, Price DD, Mayer DJ:Thermal hyperalgesia in association with the development of morphine tolerance in the rat: roles of excitatory amino acid receptors and protein kinase C.J Neuroscience 1994; 14: 2301-231217. Tejedor-Real P, Mico JA, Maldonado R, Roques BP, Gibert-Rahola J:Implication of endogenous opioid system in the learned helplessness model of depression. Pharmacology, Biochemistry & Behavior 1995; 52(1): 145-5218. Tejedor-Real P, Mico JA, Maldonado R, Roques BP, Gibert-Rahola J:Effect of mixed (RB 38A) and selective (RB 38B) inhibitors of enkephalin degrading enzymes on a model of depression in the rat. Biological Psychiatry 1993; 34(1-2): 100-719. Maddux JF, Desmond DP, Costello R:Depression in opioid users varies with substance use status.Am J of Drug & Alcohol Abuse 1987; 13(4): 375-8520. Darke S, Wodak A, Hall W, Heather N, Ward J:Prevalence and predictors of psychopathology among opioid users.British J Addiction 1992; 87(5): 771-621. 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McLachlan CD, Hay M, Coleman GJ:The effects of exercise on the oral consumption of morphine and methadone in rats.Pharmacology, Biochemistry & Behavior 1994; 48(2): 563-833. Strassman RJ, Appenzeller O, Lewy AJ, Aualls CR, Peake GT:Increase in plasma melatonin, beta-endorphin, and cortisol after a 28.5-mile mountain race: relationship to performance and lack of effect of naltrexone.J Clinical Endocrinology & Metabolism 1989; 69(3): 540-534. Affleck G, Tennen H:Construing benefits from adversity: adaptational significance and dispositional underpinnings. [Review] [85 Refs]. J Personality 1996; 64(4): 899-92235. Hubbard JE. Tracy J. Morgan SF. McKinney RE: Outcome measures of a chronic pain program: a prospective statistical study. Clinical Journal of Pain 1996; 12(4):330-7SELECTED BIBLIOGRAPHY ON BENZODIAZEPINE USE36. Lyons HR, Gibbs TT, Farb DH: Turnover and down-regulation of GABA(A) receptor alpha1, beta2S and gamma1 subunit mRNAs by neurons in culture.J Neurochem 2000; 74(3):1041-837. Nowakowska E, Chodera A, Kus K: Pharmacological aspects of withdrawal from certain benzodiazepines. Pol J Pharmocol 1997; 49(2-3): 89-9538. Toki S, Saito T, Nabeshima A, Hatta S, Watanabe M, Takahata N: Changes in GABA(A) receptor function and cross-tolerance to ethanol in diazepam-dependent rats. Alcohol Clin Exp Res 1996; 20(1 Suppl): 40A-44A39. Toki S, Saito T, Hatta S, Takahata N: Diazepam physical dependence and withdrawal in rats is associated with alteration in GABA(A) function.Life Sci 1996; 59(19): 1631-4140. Rickels K, DeMartinis N, Rynn M, Mandos L: Pharmacologic strategies for discontinuing benzodiazepine treatment. J Clin Pshchopharmacol 1999; 19 (6 Suppl 2): 12S-16S41. Skelton KH, Nemeroff CB, Knight DL, Owens MJ:Chronic administration of the triazolobenzodiazepine alprazolam produces opposite effects on corticotropin-releasing factor and urocortin neuronal systems. J Neurosci 2000; 20(3): 1240-842. Potocar J, Coupland N, Wilson S, Rich A, Nutt D: Assessment of GABA(A) benzodiazepine receptor (GBzR) sensitivity in patients on benzodiazepines.Psychopharmacology (Berl) 1999; 146(2): 180-443. Fujita M, Woods SW, Verhoeff NP, Abi-Dargham A, Baldwin RM, Zoghbi SS, Soares JC, Jatlow PA, Krystal JH, Rajeevan N, Charney DS, Seibl JP, Innis RB: Changes of benzodiazepine receptors during chronic benzodiazepine administration in humans. Eur J Pharmacol 1999; 368(2-3): 161-7244. Morin CM, Colecchi C, Stone J, Sood R, Brink D: Behavioral and pharmacological therapies for late-life insomnia: a randomized control trial. JAMA 1999; 281(11): 991-945. Lader MH:Limitations on the use of benzodiazepines in anxiety and insomnia: are they justified? Eur Neuropshchopharmacol 1999 9(Suppl 6): S399-40546. Roerig JL:Diagnosis and management of generalized anxiety disorder.J Am Pharm Assoc (Wash) 1999; 39(6):811-2147. Casacalenda N, Boulenger JP: Pharmacologic treatments effective in both generalized anxiety disorder and major depressive disorder: clinical and theoretical implications.Can J Psychiatry 1998; 43(7): 722-3048. Lader MH: The nature and duration of treatment for GAD. Acta Psychiatr Scand Suppl 1998; 393: 109-1749. Ballenger JC, Davidson JR, Lecrubier Y, Nutt DJ, Baldwin DS, den Boer JA, Kasper S, Shear MK: Consensus statement on panic disorder from the international consensus group on depression and anxiety.J Clinical Psychiatry 1998; 59 (Suppl 8): 47-5450. den Boer JA: Pharmacotherapy of panic disorder: differential efficacy from a clinical viewpoint.J Clin Psychiatry 1998; 59 (Suppl 8): 30-651. Sheikh JL, Swales PJ: Treatment of panic disorder in older adults: a pilot study comparison of alprazolam, imipramine, and placebo. Int J Psychiatry Med 1999; 29(1): 107-1752. den Boer JA, Slapp BR: Review of current treatment in panic disorder. Int Clin Psychopharmacol 1998; 13 (Suppl 4): S25-3053. van Balkom AJ, Bakker A, Spinhoven P, Blaauw BM, Smeenk S, Ruesink B: A meta-analysis of the treatment of panic disorder with or without agoraphobia: a comparison of psychopharmacological, cognitive-behavioral and combination treatments.J Nerv Ment Dis 1997; 185(8): 510-654. Nelson J, Chouinard G: Guidelines for the clinical use of benzodiazepines: Pharmacokinetics, rebound and withdrawal. Canadian Society for Clinical Pharmacology. Can J Clin Pharmacol 1999; 6(2): 69-8355. Lacerra C, MartiJena ID, Bustos SG, Molina VA: Benzodiazepine withdrawal facilitates the subsequent onset of escape failures and anhedonia: influence of different antidepressant drugs.Brain Res 1999; 819 (1-2): 40-756. Neutel CI, Patten SB: Risk of suicide after benzodiazepine and/or antidepressant use.Ann Epidemiol 1997;7(8):568-7457. Akhondzadeh S, Stone TW: Potentiation of muscimol-induced long-term depression by benzodiazepines and prevention or reversal by pregnenolone sulfate.Pharmacol Res 1998; 38(6): 441-858. Gear RW, Miaskowski C, Heller PH, Paul SM, Gordon NC, Levine JD: Benzodiazepine mediated antagonism of opioid analgesia.Pain 1997; 71(1): 25-959. Rickels K, DeMartinis N, Rynn M, Mandos L:Pharmacologic strategies for discontinuing benzodiazepine treatment.J Clin Psychopharmacol 1999; 19(6 Suppl 2): 12S-16S60. Gelpin E, Bonne O, Peri T, Brandes D, Shalev AY: Treatment of recent trauma survivors with benzodiazepines: a prospective study.J Clin Psychiatry 1996; 57(9): 390-461. Graeff FG, Guimaraes FS, De Andrade TG, Deakin JF:Role of 5-HT in stress, anxiety and depression.Pharmacol Biochem Behav 1996; 54(1): 129-41SELECTED BIBLIOGRAPHY ON THE GENETICS OF SUBSTANCE DEPENDENCE1.      Collins AC, Wehner JM, Wilson WR:Animal Models of Alcoholism: Genetic Strategies and Neruochemical Mechanisms. Institute for Behavioral Genetics, University of Colorado, Boulder 80309. Biochem Soc Symp 1993;59():173-91.2.      Devor EJ:A Developmental-Genetic Model of Alcoholism: Implications for Genetic Research. Department of Psychiatry, University of Iowa Hospitals and Clinics, Iowa City 52242-1057. J Consult Clin Psychol, 1994,Dec;62(6):1108-15.3.      Froehlich JC:Genetic Factors in Alcohol Self-Administration. Department of Medicine, Indiana University School of Medicine, Indianapolis 46202, USA. J Clin Psychiatry 1995;56 Suppl 7():15-23.4.      Gianoulakis C, de Waele JP:Genetics of Alcoholism: Role of The Endogenous Opioid System. Douglas Hospital Research Centre, Montreal, Quebec, Canada. Metabolic Brain Disease. 9(2):105-31, 1994 Jun.5.      Goldman D:Recent Development in Alcoholism: Genetic Transmission. Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892. Recent Dev Alcohol 1993;11():231-48.6.      Guitart X, Lumeng L, Li TK, Nestler EJ:Alcohol-Preferring and Nonpreferring Rats Display Different Levels of Neurofilament Proteins in The Ventral Tegmental Area. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. Alchol Clin Exp Res 1993Jun;17(3):580-5.7.      Hill SY:Vulnerability to Alcoholism in Women, Genetic and cultural factors. Department of Psychiatry, University of Pittsburgh School of Medicine, PA 15213, USA. Recent Developments in Alcoholism. 12:9-28, 1995.8.      Dendler KS, Neale MC, Heath AC, Kessler RC, Eaves LJ:A Twin Family Study of Alcoholism in Women. Department of Psychiatry, Medical College of Virginia/Virginia Commonwealth University 23298-0710. Am J Psychiatry, 1994May;151(5):707-159.9.      Knop J: Familial Alcoholism: Family, Twin, Adoption and High Risk Studies. Department of Psychiatry, Gentofte University Hospital, Hellerup, Denmark. EXS, 1994;71:121-31.10.  Li TK, Lumeng L, Doolittle DP:Selective Breeding for Alcohol Preference and Associated Responses. Department of Medicine, Indiana University School of Medicine, Indianapolis 46202-5124. Behavior Genetics, 23(2):163-70,1993, Mar.11.  Li TK, Lumeng L, McBride WJ, Murphy JM:Genetic and Neurobiological Basis of Alcohol-Seeking Behavior. Indiana University School of Medicine, Indianapolis. Alcohol Alcohol, 1994 Nov;29(6):697-700.12.  Nestler EJ, Guitart X, Ortiz J, Trevisan L:Second Messenger and Protein Phosphorylation Mechanisms Underlying Possible Genetic Vulnerability to Alcoholism. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. Ann N Y Acad Sci, 1994 Feb 28;708():108-18.13.  Robledo P, Lumeng L, Li TK, Ehlers CL:Effects of MK 801 and Diazepam on The EEG of P and NP Rats. Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037. Alcohol Clin Exp Res, 1994 Apr;18(2):363-8.14.  Rommelspacher H, Sllstrom Baum S, Dufeu P, Schmidt LG:Determination of (R)- and (S)- Salsolinol Sulfate and Dopamine Sulfate Levels in Plasma of Nonalcoholics and Alcoholics. Berlin-Ulmenallee 30, Germany. Alcohol, 1995 Jul-Aug;12(4).15.  Schuckit MA:A Clinical Model of Genetic Influences in Alcohol Dependence. Department of Psychiatry, Veterans Affairs Medical Center, San Diego, California 92161. J Stud Alcohol, 1994 Jan;55(1):5-17.16.  Self DW. Nestler EJ:Molecular Mechanisms of Drug Reinforcement and Addiction. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA. Annual Review of Neuroscience. 18:463-95, 1995.17.  Schork NJ, Schork CM:Issues and strategies in the genetic analysis of alcoholism and related addictive diseases. Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109-1998, USA. Alcohol. 16(1):71-83 1998 Jul.18.  Foroud T, Li TK: Genetics of alcoholism: a review of recent studies in human and animal models. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202, USA Am J Addict 1999; 8($): 261-7819.  Reich T, Hinrichs A, Culverhouse R, Bierut L:Genetic studies of alcoholism and substance dependence. Department of Psychiatry, Washington University, St. Louis, MO 63110-1026 Am J Hum Genet 1999; 65(3): 599-60520.  Li TK:Pharmacogenetics of responses to alcohol and genes that influence alcohol drinking. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202, USA J Stud Alcohol 2000; 61(1): 5-12Updated Citations Re: OpiatesLaulin JP, Celerier E, Larcher A, Le Moal M, Simonnet G. Opiate tolerance to daily heroin administration: an apparent phenomenon associated with enhanced pain sensitivity. Neuroscience 1999; 89(3): 631-6Kayser V, Besson JM, Guilbaud G. Paradoxical hyperalgesic effect of exceedingly low doses of systemic morphine in an animal model of persistent pain (Freund’s adjuvant-induced arthritic rats). Brain Res. 1987; 414(1): 155-7Ta LE, Dionne RA, Friction JR, Hodges JS, Kajander KC. SYM-2081 a kainite receptor antagonist reduces allodynia and hyperalgesia in a freeze injury model of neuropathic pain. Brain Res. 2000; 858(1): 106-20Compton P; Charuvastra VC; Kintaudi K; Ling W Pain responses in methadone-maintained opioid abusers.J Pain Symptom Manage 2000 Oct;20(4):237-45Borgland SL. Acute opioid receptor desensitization and tolerance: is there a link? Clin Exp Pharmacol Physiol. 2001 Mar;28(3):147-54.Ciccone DS, Just N, Bandilla EB, Reimer E, Ilbeigi MS, Wu W. Psychological correlates of opioid use in patients with chronic nonmalignant pain: a preliminary test of the downhill spiral hypothesis. J Pain Symptom Manage. 2000 ep;20(3):180-92.Doverty M, Somogyi AA, White JM, Bochner F, Beare CH, Menelaou A, Ling W. Methadone maintenance patients are cross-tolerant to the antinociceptive effects of morphine. Pain. 2001 Aug;93(2):155-63.Celerier E, Laulin JP, Corcuff JB, Le Moal M, Simonnet G. Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration: a sensitization process. Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration: a sensitization process. J Neurosci. 2001 Jun 1;21(11):4074-80.Rosenblum A, Joseph H, Fong C, Kipnis S, Cleland C, Portenoy RK. Prevalence and characteristics of chronic pain among chemically dependent patients in methadone maintenance and residential treatment facilities. JAMA. 2003 May 14;289(18):2370-8.Collins ED, Streltzer J. Should opioid analgesics be used in the management of chronic pain in opiate addicts? Psychosomatics. 1999 May-Jun;40(3):226-32.Vanderah TW, Suenaga NM, Ossipov MH, Malan TP Jr, Lai J, Porreca F. Tonic descending facilitation from the rostral ventromedial medulla mediates opioid-induced abnormal pain and antinociceptive tolerance. J Neurosci. 2001 Jan 1;21(1):279-86. Li, X; Angst, M S; Clark, J D. Opioid-induced hyperalgesia and incisional pain. Anesth Analg. 2001 Jul; 93 Supplement: (1):204-9.Celerier, E; Laulin, J P; Corcuff, J B; Le Moal, M; Simonnet, G. Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration: a sensitization process. J Neurosci: 2001 Jun; 21(11):4074-80.Doverty, M; White, J M; Somogyi, A A; Bochner, F; Ali, R; Ling, W. Hyperalgesic responses in methadone maintenance. Pain: 2001 Feb 1; 90(1-2):91-6.Laulin, J P; Celerier, E; Larcher, A; Le Moal, M; Simonnet, G. Opiate tolerance to daily heroin administration: an apparent phenomenon associated with enhanced pain. Neuroscience: 1999 Mar: 89(3):631-6.Kayser, V; Besson, J M; Guilbaud, G. Paradoxical hyperalgesic effect of exceedingly low doses of systemic morphine in an animal model of persistent pain (Freund's adjuvant-induced arthritic rats). Brain Res: 1987 Jun 23: 414(1):155-7. ASAM

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