DAVID TAUBEN, MD Clinical Associate Professor Anesthesia & Pain Medicine Medicine University of Washington. Antidepressant Analgesia

Transcription

1 DAVID TAUBEN, MD Clinical Associate Professor Anesthesia & Pain Medicine Medicine University of Washington Antidepressant Analgesia

2 Pain is:

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4 EXPERIENCE OF WELL-BEING PAIN SUFFERING INJURY OR DISEASE COPING PERSONALITY LIFE HISTORY BIOGENETIC PROCESSES AFFECTIVE PROCESSES COGNITIVE PROCESSES INTERPERSONAL PROCESSES

5 Descending Inhibition ROSTROVENTRAL MEDULLA (RVM) NORADRENALINE (NA) SEROTONIN (5-HT) DORSAL HORN NORADRENALINE (NA) SEROTONIN (5-HT) PRIMARY AFFERENT FIBER (PAF) PROJECTION NEURON/DORSAL HORN (PN) PARABRACHIAL NUCLEUS (PBN) DORSORETICULAR NUCLEUS (DRT) NUCLEUS TRACTUS SOLITARIS (NTS) PERIAQUADUCTAL GREY (PAG) AMYGDALA & HYPOTHALAMUS Millan MJ., Prog Neurobio 2002; 66: 375.

6 DORSAL HORN MODULATION Monoamines NA (-1/-2) 5-HT DA Enkephalin (ENK) -Endorphin (-EP) Acetylcholine (ACH) Cannabinoids (CB) Nitric oxide (NO) Prostaglandins (PG) Millan MJ., Prog Neurobio 2002; 66: 363.

7 3 Pain Types 1. Incidental Activation of nociceptors without tissue damage 2. Nociceptive Traditional pain pathways involved at tissue and nerve cell level Local sensitization mechanisms 3. Neuropathic/Central Neuronal tissue or nerve injury Injury may no longer be required to maintain pain Abnormally behaving neurons throughout the central nervous system: Abnormal brain physiology Non-dermatomal, since pathologically functioning anatomy

8 Pharmacologic options:

9 Antidepressant Pain Targets Verdu B, et al. Drugs 2008; 68;

10 Co-morbidity of Depression and Pain 30-54% incidence of depression with chronic pain 45-95% (overall prevalence 69%) patients with depression report only somatic pain complaints 50% depressed patients present with multiple unexplained somatic complaints 11% depressed patients deny any psychological symptoms of depression Significantly more common when patients had no ongoing relation with a PCP Simon GE., et al. N Engl J Med 1999;341:

11 Monoamines and Depression (1): Serotonin (5-HT) Reduced levels in depression 5-HT and its metabolite 5-HIAA Postmortem brain tissue levels CSF 5-HIAA, especially among suicidal 5-HT transporter binding sites and serotonin uptake by platelets and brain tissues Increased density of 5-HT 2 binding sites in both brain tissue and platelets in depressed patients Fava, M. J Clin Psychiatry 2003;64(S 13):26-29 Fishbain, DA., Cutler, Rosomoff HL., et al Clin J Pain 1997;13:

12 Monoamines and Depression (2): Serotonin (5-HT) All drugs that selectively inhibit the reuptake of 5-HT are effective in the treatment of depression Inhibition of 5-HT synthesis in treated depressed patients who exhibit a response to 5-HT reuptake inhibitors produces a rapid relapse of depression All currently available anti-depressant treatments including electroconvulsive therapy increase 5-HT Fava, M. J Clin Psychiatry 2003;64(S 13):26-29 Fishbain, DA., Cutler, Rosomoff HL., et al Clin J Pain 1997;13:

13 Monoamines and Depression (1): Noradrenaline (NA) With depression: Reduced CSF NA Reduced NA in plasma and urine Sensitization & up-regulation of -adrenergic receptors Increased -adrenergic receptor density in postmortem brain -2 adrenoreceptor activity required for TCA effect Fishbain, DA, Cutler, Rosomoff H, et al Clin J Pain 1997;13: McCleane, Gary, CNS Drugs 2008

14 Monoamines and Depression (2): Noradrenaline (NA) Tricylic antidepressants (TCAs): Raise concentrations of NA Reuptake blocking and/or inhibiting catalysis Increased synaptic availability of NA Desensitize NA-- adrenoceptor-coupled-adenylate cyclase system Similar mechanisms with all other effective antidepressant treatments including ECT Fishbain, DA, Cutler, Rosomoff H, et al Clin J Pain 1997;13: McCleane, Gary, CNS Drugs 2008

15 Theories of Linkage between Pain and Depression Depression precedes pain: Antecedent Data inconclusive: Against Favor Depression is response to pain: Consequence Uniform data strongly support Severity corresponds Prediposed by psychiatric history and genotype: Scar Data inconclusive Experiential mediators: Cognitive Behavioral Life interference/loss of control Evidence strongly supports Distortions increase severity depression Fishbain, DA., Cutler, Rosomoff HL., et al. Clin J Pain 1997;13:

16 Cognitive Behavioral Group Therapy: Reduced regional cerebral blood flow by PET A B Responders (n = 9) Responders < Nonresponders (n = 9/9) Responders to CBGT Responders < Non-responders Furmark T, et al. Arch Gen Psychiatry 2002; 59:

17 Anxiogenic public speaking: Cerebral Blood Flow Response Areas of significant decrease in regional blood flow response Between-group differences in amount of change with treatment CBGT (n = 6) Citalopram (n = 6) Responders (n = 9) CBGT Citalopram Overlap Furmark T, et al. Arch Gen Psychiatry 2002; 59: CBGT Citalopram Overlap

18 Monoamines and Pain Principal neurotransmitters in descending inhibitory systems : PAG and RVM stimulation produce analgesia Stimulation brain stem releases spinal cord serotonin and noradrenaline Serotonin depletion increases rat pain Analgesia from intrathecal serotonin agonists blocked by NA depletion Mixed analgesic responses with differing NA-2 receptor sub-type agonist/antagonists

19 Dorsal Horn: Serotonin receptor modulation Primary afferent fibers (PAF) Projection interneurons (PN) Inhibitory interneurons (ININ) Millan MJ., Prog Neurobio 2002; 66: 375.

20 Dorsal horn: Noradrenaline receptor modulation Primary afferent fibers (PAF) Projection interneurons (PN) Inhibitory interneurons (ININ) Millan MJ., Prog Neurobio 2002; 66: 375.

21 Dorsal Horn: Dopamine receptor modulation Primary afferent fibers (PAF) Projection interneurons (PN) Inhibitory interneurons (ININ) Millan MJ., Prog Neurobio 2002; 66: 388.

22 Mechanisms of Antidepressant Action Verdu B. Drugs 2008;

23 Clinical Trials for TCA Effectiveness: Positive Evidence Post Herpetic Neuralgia NNT Diabetic Peripheral Neuropathy NNT Painful Mono and Polyneuropathy Atypical Facial Pain NNT Fibromyalgia/Central Pain NNT 1.7 Post-op Breast Cancer Pain 30% vs 72% Osteroarthritis Low Back Pain Limited or no evidence Spinal Cord Injury HIV related neuropathy Phantom Limb Burning Mouth No effect with trazadone Saarto T, Wiffen PJ. Cochrane Database of Systematic Reviews 2007

24 Clinical Trials SNRI Effectiveness: Diabetic Neuropathy Duloxitene Fibromyalgia Venlafaxine Duloxitene Milnacipran

25 Analgesic Effectiveness of SSRIs: Overall NNT 5-15 Painful Diabetic Neuropathy Fibromyalgia 1. Imipramine > Paroxetine 2. Desipramine 61% > Fluoxetine 48% > Placebo 41% 3. Citalopram reduces pain and improves mood No difference from placebo

26 Other Antidepressants Bupropion Inhibits reuptake of norepinehrine and dopamine Effective in various central and peripheral neuropathies Tetracyclic: Mirtazapine -2 adrenoreceptor antagonist Tetracyclic: Maprotiline NA Selective

27 Antidepressant Analgesic Efficacy ScienceDirect - Full Size Table 9/13/09 1:51 PM CLOSE Table 1. Analgesic efficacy of antidepressants Antidepressant Animals a Humans b Number of studies Positive results Number of studies Combined NNT c TCAs 126 Acute pain tests 81% Chronic pain models 95% SSRIsd 39 Acute pain tests 44% Chronic pain models 33% SNRIse 10 Acute pain tests 100% Others Chronic pain models 100% f 7 Acute pain tests 100% (bupropion: only one study) Chronic pain models 100% a Data adapted from Ref. [31] and complete up to Only models. b Data from Ref. [9]. 10% of the animal studies were performed using chronic pain c Number of patients treated to improve the health of one patient (at least 50% decrease in pain intensity). d For example, fluoxetine, fluvoxamine, sertraline, paroxetine and citalopram. e For example, venlafaxine, minalcipran, duloxetine. f For example, mirtazapine, bupropion. _urlversion=0&_userid=582538&md5=07689f6dda7230ab4c5b87c234509e44 Page 1 of 1 Micó JA, Ardid D, Berrocoso E, Eschalier A. Antidepressants and pain. Trends Pharm Sci 2006

28 Standardized mean difference in pain improvement for patients undergoing antidepressant therapy Salerno, S. M. et al. Arch Intern Med 2002;162: Copyright restrictions may apply.

29 Antidepressant Analgesia: Clinical Summary Noradrenergic vs. Serotonergic vs. Mixed Tricyclics > SNRIs > SSRIs TCAs pain gold standard Mixed agents show efficacy in 80% of non-depressed patients

30 " NA and 5-HT Reuptake Selectivity Highly noradrenergic Mixed Highly selective serotonin Desipramine/Nortriptyline/ Protriptyline Imipramine/ Amitriptyline Doxepin Mirtazapine/Milnacipran Duloxitine 10 fold serotonin > NE Venlafaxine 30 fold serotonin > NE Citalopram Fluoxetine Sertraline Fluvoxamine

31 Antidepressant Toxicities Arrhythmia > NA specific & existing cardiac disease Delayed depolarization Dose-dependant depressant effect Muscarinic Anticholinergic Blockade: Dry mouth Urinary retention Constipation Antihistaminic: Sedative: Use as sleep aid Weight gain Adrenoreceptor -1 blockade Orthostatic hypotension Bradycardia Serotonin syndrome Flushing/Sweating/Hyperthermia Tachycardia/Hypertension Diarrhea/Vomiting Agitation/Delirium Libido impairment/ anorgasmia SSRI: Increased GI cytotoxity when taken with NSAID Epileptogenic Bupropion (above 600 mg) Tramadol plus antidepressant Psychiatric Mania Suicidality

32 Antidepressants in Pain: Dosing Guidelines 50% of antidepressant level dose Go low and go slow TCA added to SSRI raises effective level by 60% Monitor measured blood level of tricyclics Toxicity increases with sedatives, alcohol, opioids Use lowers opioid requirements

33 Antidepressant Dosing (typical mg/24h): Tricyclics 3 o amines Amitriptyline (10-150) Cyclobenzaprine (10-30) = Flexeril Doxepin (10-150) Imipramine (10-150) Tricyclics 2 o amines Nortriptyline (10-75) Desipramine (10-50) Mixed SNRI: Venlafaxine (25-225) Duloxitine (20-60) Milnacipran ( ) Mixed receptor (5-HT/NE/ ): Tramadol (50-200) Adverse interaction with all other antidepressant Rx

34 Antidepressant Dosing (typical mg/24h): SSRIs: Fluoxetine (10-40) Sertraline (25-200) Paroxitene (10-40) Citalopram (10-60) Lexapro (? Value added) Trazodone (25-600) Other: Bupropion (75-450) DA/NA reuptake inhibitor Mirtazapine (15-450) 5-HT 2A /5-HT 2C /NA (α-2) receptor blockade

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36 References (1) 1. Anderson, I., Ferrier, I., Baldwin, R., Cowen, P., Howard, L., Lewis, G., et al. Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 2000 British Association for Psychopharmacology guidelines. Journal of Psychopharmacology 2008;22 (4): Dworkin RH, O Conner AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, Kalso EI, Loeser JD, Miaskowski C, Nurmikko TJ, Portnoy RK, Rice ASC, Stacey BR, Treede, R-D, Turk, DC, Wallace MS. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007; 132: Fava, M The role of the serotonergic and noradrenergic neurotransmitter systems in the treatment of psychological and physical symptoms of depression. J Clin Psychiatry 2003;64(S 13): Finnerup NB,, Sindrup SH, Jensen TS, Chronic neuropathic pain: mechanisms, drug targets and measurements Fund & Clin Pharm 2007; 21: Fishbain, DA., Cutler, Rosomoff HL., et al. Chronic pain-associated depression: antecedent or consequence of chronic pain? A review. Clin J Pain 1997;13: Furmark T, Tillfors M, Marteinsdottir I, Fischer H, Pissiota A, Langstrom B, Fredrikson M. Common changes in cerebral blood flow in patients with social phobia treated with citalopram or cognitive-behavioral therapy. Arch Gen Psychiatry 2002;59: Jann MW, Slade JH. Antidepressants for the treatment of chronic pain and depression. Pharmacotherapy 2007; 27:

37 References (2) 8. McCleane G. Antidepressants as analgesics. CNS Drugs 2008; 22: Micó JA, Ardid D, Berrocoso E, Eschalier A. Antidepressants and pain. Trends Pharm Sci 2006; 27: Millan MJ. Descending Control of Pain. Progress in Neurobiology 2002; 66: Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD DOI: / CD pub Salerno Arch Int Med 13. Simon GE., VonKorff M., Piccinelli M., et al., An international study of the relation between somatic symptoms and depression. N Engl J Med 1999;341: Sindrup SH, Otto M, Finnerup NB, et al. Antidepressants in the treatment of neuropathic pain. Basic Clin Pharmacol Toxicol 2005; 96: Verdu, B., Decosterd, I., Buclin, T., Stiefel, F., & Berney, A. (2008). Antidepressants for the Treatment of Chronic Pain. Drugs. 68 (18), Villanueva, Luis PaIn 2009;143: Yalcin I, Tessier L-H, Petit-Demoulière N, Dorido, S, Hein L, Freund-Mercier M-J, Barrota M. 2-adrenoceptors are essential for desipramine, venlafaxine or reboxetine action in neuropathic pain. Neuro Dis 2009;33: