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American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition, Text Revision. DSM-IV TR. Washington : APA 2000.

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American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition, Text Revision. DSM-IV TR. Washington : APA 2000.

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Presentation on theme: "American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition, Text Revision. DSM-IV TR. Washington : APA 2000."— Presentation transcript:

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2 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition, Text Revision. DSM-IV TR. Washington : APA DSM-IV criteria of Major Depressive Episode 3 Depression Today Diagnostic Criteria 1. Depressed mood 2. Loss of interest or pleasure in all, or almost all, usual activities 3. Significant weight loss or weight gain 4. Insomnia or hypersomnia 5. Psychomotor agitation or retardation 6. Fatigue or loss of energy 7. Feelings of worthlessness or excessive or inappropriate guilt 8. Diminished ability to think or concentrate or indecisiveness 9. Recurrent thoughts of death or suicide Five (or more) symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.

3 Healy D, McMonagle T. The enhancement of social functioning as a therapeutic principle in the management of depression. J Psychopharmacol 1997;11(4, Suppl):S25-S31. A depletion or reduced activity of cerebral noradrenaline and serotonin Symptoms of depression Serotonergic Noradrenergic AND - Agitation - Loss of appetite - Decreased libido - Suicidal ideation - Aggressive behaviour (oral or physical) - Irritability - Depressed mood - Loss of interest or pleasure - Insomnia or hypersomnia - Feeling of worthlessness - Anxiety - Pessimism - Decreased concentration - Retardation - Loss of energy - Lassitude - Tiredness - Reduced self-care (hygiene) Depression Today Physiopathology The aminergic theory of depression 7

4 Pharmacology and Pharmacokinetics

5 15 Milnacipran's Pharmacology and Pharmacokinetics What is milnacipran ? (1RS) Z-2aminomethyl – 1 – phenyl – N, N – diethylcyclopropane - carboxamide hydrochloride O N NH 2 HCl Milnacipran hydrochloride

6 Milnacipran's Pharmacology and Pharmacokinetics Mechanism of action A well balanced SNRI 16 to Dual Action Drugs efficacy (-) tolerance (+) TCAs to Mono selective drugs TCA NA5-HT 1 H1H1 ACh SSRI 5-HT SNRI Milnacipran NA5-HT efficacy (+) tolerance (+)

7 * Selectivity ratios for reuptake inhibitors measured in vitro 17 A well balanced SNRI Tran PV et al. Dual monoamine modulation for improved treatment of major depressive disorder. J Clin Psychopharmacology 2003;23: CompoundRatio NA / 5-HT* Mirtazapine0.05 Desipramine0.05 Milnacipran1.6 Amitriptyline8.1 Duloxetine9.4 Imipramine26.4 Venlafaxine30.2 Clomipramine135.7 Fluoxetine296.3 Milnacipran's Pharmacology and Pharmacokinetics Mechanism of action

8 A selective mechanism of action 25 Absence of binding to post-synaptic receptors Milnacipran IC 50 > nM on over 40 receptors studied Puozzo C et al. Pharmacology and pharmacokinetics of milnacipran. Int Clin Psychopharmacol 2002; 17(Suppl 1):S25-S35. Milnacipran's Pharmacology and Pharmacokinetics Mechanism of action Affinity for monoamine receptors IC 50 (nM) muscarinic alpha 1 H 1 Milnacipran > > > Imipramine

9 A selective mechanism of action Absence of binding to post-synaptic receptors 26 ReceptorClinical benefit in case of absence of binding to receptor Alpha and beta adrenergicCardiovascular safety CholinergicNo anticholinergic effects (constipation and dry mouth) Histaminergic H 1 No sedation and weight gain Milnacipran's Pharmacology and Pharmacokinetics Mechanism of action

10 28 Excellent oral absorption (> 90%) No effect of meals on absorption Linear relationship dose - plasma levels Ease of dose adjustment Relatively short half-life (8 h) Rapid establishment of steady-state levels Low protein binding (13%) Rare drug interactions Low inter-individual variation Milnacipran's Pharmacology and Pharmacokinetics Pharmacokinetics

11 31 Inhibition of CYP 450 subtypes FLUVFLUOX/ NORFLUOX PAROXSERTVENLADULOXMILNA Substrate 1A theophylline, TCAs, melatonin, clozapine, haloperidol 2C benzodiazepines, propranolol, TCAs, proton pump inhibitor 2C NSAIDs 2D TCAs, antipsychotics, beta- blockers, anti- arrhythmics 3A antibiotics, antivirals, benzodiazepines, calcium antagonists No liver metabolism by cytochrome P-450 (1) Yamane K. Clinical efficacy of the SNRI milnacipran on a depressive state in a department of neurology Abstr. (2) (3) Cupp MJ, Tracy TS. Cytochrome P450 : new nomenclature and clinical implications. Am Fam Physician 1998;57(1): (4) Prescribing Information Cymbalta®. Milnacipran's Pharmacology and Pharmacokinetics Pharmacokinetics FLUV: fluvoxamine; FLUOX/NORFLUOX: fluoxetine/norfluoxetine; PAROX: paroxetine; SERT: sertraline; VENLA: venlafaxine; MILNA: milnacipran; DULOX: duloxetine

12 Efficacy in Major Depression

13 Comparative studies vs SSRIs in moderate to severe depression 2 major double-blind studies comparing Milnacipran with SSRIs in major depression Population Adults Inpatients SSRIs Fluoxetine, Fluvoxamine Studies carried out in Europe Lopez-Ibor J et al. Milnacipran and selective serotonin reuptake inhibitors in major depression. Int Clin Psychopharmacol 1996;11(Suppl 4):S41-S Milnacipran's Efficacy in Major Depression Efficacy vs SSRIs

14 52 Lopez-Ibor J et al. Milnacipran and selective serotonin reuptake inhibitors in major depression. Int Clin Psychopharmacol 1996;11(Suppl 4):S41-S46. Meta-analysis of double-blind studies in moderate to severe depression Change in total HDRS score between baseline and endpoint * p<0.05 HDRSMilnacipran (n=150) SSRIs (n=156) at baseline at endpoint at endpoint -15.1*-12.2 Milnacipran's Efficacy in Major Depression Efficacy vs SSRIs Milnacipran : a superior improvement in HDRS score

15 53 Lopez-Ibor J et al. Milnacipran and selective serotonin reuptake inhibitors in major depression. Int Clin Psychopharmacol 1996;11(Suppl 4):S41-S46. Milnacipran's Efficacy in Major Depression Efficacy vs SSRIs Meta-analysis of double-blind studies in moderate to severe depression Response : reduction in HDRS score of at least 50%. Remission : total HDRS score 7 at endpoint Responders Remitted * p<0.01 SSRIs (fluvoxamine 100 mg BID or fluoxetine 20 mg OD) (n=156) Milnacipran 50 mg BID (n=150) % patients %* 50% 39% 28% Higher response and remission rates vs SSRIs

16 60 Comparative study vs Paroxetine in ambulatory patients with mild to moderate depression Depressed outpatients Major depression (DSM-IV) 2 parallel groups Milnacipran 50 mg BID (n=150) Paroxetine 20 mg OD (n=153) Measures HDRS 17, MADRS, predictors of response, discontinuation emergent symptoms Follow-up : 6 weeks Milnacipran's Efficacy in Major Depression Efficacy vs SSRIs Sechter D et al. A comparative study of milnacipran and paroxetine in outpatients with major depression. J Affect Disord 2004;83:

17 61 Change in total HDRS score between baseline and endpoint (ITT population-LOCF) Baseline HDRS 17 score Milnacipran (n=148) Paroxetine (n=151) days Sechter D et al. A comparative study of milnacipran and paroxetine in outpatients with major depression. J Affect Disord 2004;83: Milnacipran's Efficacy in Major Depression Efficacy vs SSRIs Comparative study vs Paroxetine in ambulatory patients with mild to moderate depression

18 62 Response : reduction in HDRS or MADRS score of at least 50% Paroxetine 20 mg OD Milnacipran 50 mg BID HDRS 17 MADRS p=0.70 p=0.71 % responders Milnacipran's Efficacy in Major Depression Efficacy vs SSRIs Comparative study vs Paroxetine in ambulatory patients with mild to moderate depression Sechter D et al. A comparative study of milnacipran and paroxetine in outpatients with major depression. J Affect Disord 2004;83:

19 63 Predictive factors of Milnacipran CGI responder rate according to psychomotor retardation at baseline (1) Sechter D et al. A comparative study of milnacipran and paroxetine in outpatients with major depression. J Affect Disord 2004;83: (2) Bisserbe JC. Clinical utility of milnacipran in comparison with other antidepressants. Int Clin Psychopharmacol 17 (Suppl 1):S43-S50. HDRS Retardation item a t baseline ALL<1< 2<3 % CGI responders Paroxetine 20 mg OD Milnacipran 50 mg BID p= Milnacipran's Efficacy in Major Depression Efficacy vs SSRIs Comparative study vs Paroxetine in ambulatory patients with mild to moderate depression

20 Venlafaxine => SSRI at low doses, SNRI only at higher doses (> 150 mg/day) => requires dose-titration to bring in NA activity and true SNRI dose less well tolerated than SSRIs Milnacipran => SNRI at all doses (well balanced reuptake inhibition of 5-HT and NA whatever the dose) => no dose-titration required for NA activity and all doses as well tolerated as SSRIs 66 (1) Puozzo C et al. Pharmacology and pharmacokinetics of milnacipran. Int Clin Psychopharmacol 2002;17(Suppl 1):S25-S35. (2) Briley M. The logical evolution towards dual action antidepressants. Drugs in Focus 2001;3:5-10. (3) Moret C, Briley M. Effects of milnacipran and pindolol on extracellular noradrenaline and serotonin levels in guinea pig hypothalamus. J Neurochem 1997;69: Milnacipran's Efficacy in Major Depression Efficacy vs Venlafaxine

21 Tolerance and Safety

22 No stimulant or sedative effect Positive effect on vigilance and cognition No alteration of ability to drive a car No potentiation of alcohol effects No effect on seizure threshold No alteration sleep pattern (EEG) A good tolerance profile 81 (1) Hindmarch I et al. Pharmacodynamics of milnacipran in young and elderly volunteers. Br J Clin Pharmacol 2000;49: (2) Richet F et al. Effects of milnacipran on driving vigilance. Int J Psychiatr Clin Pract 2004 (in press). Milnacipran's Tolerance and Safety Overall tolerability No weight modification Minimal sexual dysfunction No effect on cardiac conduction or ventricular depolarisation

23 associated with milnacipran therapy 83 Minimal sexual dysfunction Montgomery SA. The place of milnacipran in clinical practice. Int Clin Psychopharmacol 2003;18(Suppl 1):S1-S9. Milnacipran's Tolerance and Safety Sexual function very low (< 2%) spontaneous reports of sexual dysfunction in clinical trials very low frequency suggested by feedback from prescribing clinicians

24 84 No effect on cardiac conduction or ventricular depolarisation During clinical trials : associated with milnacipran therapy Cardiovascular safety Milnacipran's Tolerance and Safety Cardiovascular safety a mean increase in heart rate of approximately 3 beats per minute negligible changes in arterial blood pressure

25 >70% of events rated as mild to moderate 67% of affected patients continued treatment in spite of adverse effects Clinical experience has shown that symptoms of male dysuria can be adequately controlled by using an α 1 -blocker 85 Dysuria All patients (n=1871) Males (n=529) Females (n=1342) Dysuria44 (2.35%)42 (7.94%)2 (0.15%) Retention12 (0.64%)11 (2.08%)1 (0.07%) Puech A et al. Milnacipran, a new serotonin and noradrenaline reuptake inhibitor : an overview of its antidepressant activity and clinical tolerability. Int Clin Psychopharmacol 1997;12: Milnacipran's Tolerance and Safety Dysuria

26 86 A significant improvement of objective sleep parameters Lemoine P, Faivre Th. Subjective and polysomnographic effects of milnacipran on sleep in depressed patients. Hum Psychopharmacl Clin Exp 2004;19:1-5. Milnacipran's Tolerance and Safety Sleep associated with the clinical improvement of depression Polysomnographic resultsBaselineDays 4-6Days Total sleep time (min) * Stage I sleep (min) (% of total sleep)44 (13.3%)44 (11.7%)49 (12.2%) Stage II sleep (min) (% of total sleep)190 (57.4%)240** (64.0%)243* (60.3%) Stage III and IV(slow wave) sleep (min) (% of total sleep) 27 (8.2%)33 (8.8%)42 (10.4%) REM sleep (min) (% of total sleep)70 (21.2%)58 (15.5%**)69 (17.1%*) REM latency (min)4377**80** Mean REM episode duration (min) Sleep efficiency index *84.5* Sleep latency (min)4324**27 Intrasleep awake time (min/h) Number of awakenings (a) per hour *p<0.05; **p<0.01 vs baseline (Students t-test); (a) at least 1 minute in awake sleep stage

27 visual and auditory vigilance tests 87 No effects on vigilance as evaluated by laboratory tests Richet F et al. Effects of milnacipran on driving vigilance. Int J Psych Clin Pract 2004;8: Milnacipran's Tolerance and Safety Driving vigilance Before treatment MilnacipranPlacebo Visual vigilance Number of good responses (to 45 stimuli) 43.6 ± ± ± 0.8 Mean time of good responses (1/100 s) 63.0 ± ± ± 17.0 Tiredness index ± ± ± 14.5 Auditory vigilance Number of good responses (to 45 stimuli) 43.2 ± ± ± 1.2 Mean time of good responses (1/100 s) 96.1 ± ± ± 24.9 Tiredness index-11.5 ± ± ± 27.4 Values are means ± SD

28 88 No effects on vigilance in a real driving situation Richet F et al. Effects of milnacipran on driving vigilance. Int J Psych Clin Pract 2004;8: Milnacipran's Tolerance and Safety Driving vigilance evaluation of driving tests by instructor Values are means ± SD Before treatment MilnacipranPlacebo Adaptation to driving (160 points) ± ± 17.3 Adaptation to the size of vehicle (60 points) 38.8 ± ± ± 4.3 Adaptation to traffic conditions (80 points) 45.0 ± ± 9.0 Attitude and behaviour at the steering-wheel (20 points) 12.0 ± ± ± 2.1 Global note (320 points) ± ± ± 23.1

29 92 Lower with milnacipran than SSRIs Incidence of adverse events Lopez-Ibor J et al. Milnacipran and selective serotonin reuptake inhibitors in major depression. Int Clin Psychopharmacol 1996;11(Suppl 4):S41-S46. % occurrence Milnacipran's Tolerance and Safety Adverse events vs SSRIs Milnacipran SSRIs Somnolence Fatigue Vomiting Anxiety Constipation Abdominal pain Dry mouth Headache Nausea

30 94 Incidence of treatment discontinuation emergent symptoms Sechter D et al. A comparative study of milnacipran and paroxetine in outpatients with major depression. J Affect Disord 2004;83(2-3): Milnacipran's Tolerance and Safety Adverse events vs SSRIs Lower with milnacipran than paroxetine % occurrence Milnacipran (n=46) Paroxetine (n=44) Dizziness Paranoia Depression Aggravated depression Nervousness Insomnia Anxiety Convulsions Patients with at least one symptom : Milnacipran 13% vs Paroxetine 31.8% (p=0.032)

31 (1) Kasper S et al. Comparative studies with milnacipran and tricyclic antidepressants in the treatment of patients with major depression : a summary of clinical trials. Int Clin Psychopharmacol 1996;11(4): (2) Feighner JP. The role of venlafaxine in rational antidepressant therapy. J Clin Psychiatry 1994;55 Suppl A: Lower with milnacipran than venlafaxine Incidence of adverse events Milnacipran's Tolerance and Safety Adverse events vs Venlafaxine % occurrence Milnacipran Venlafaxine Sweating Nervousness Drowsiness Constipation Dizziness/Vertigo Dry mouth Somnolence Nausea

32 96 A reduction over time Incidence of adverse events 0-3 months (n=1010) 3-6 months (n=1010) 6-9 months (n=715) 9-12 months (n=237) >12 months (n=189) Nausea Headache Constipation Dry mouth Perspiration Insomnia Abdominal pain Vertigo % occurrence Data on file. Milnacipran's Tolerance and Safety Long-term tolerability

33 TCAsSSRIsVenlafaxineMilnacipran Nausea+++++ Sexual dysfunction++ +- Weight gain++-+- Sedation++--- Sweating+++ + Constipation++--- Dry mouth++--- Dysuria+-++ Sustained hypertensionYESNOYESNO Orthostatic intoleranceYESNOYESNO QT ProlongationYESNOYESNO Treatment discontinuation for adverse events 21-33%12-20%11-19%7.6% 99 Improved tolerance profile versus other classes (1) Deakin B, Dursun S. Optimizing antidepressant treatment : efficacy and tolerability. Int Clin Psychopharmacol 2002;17 (Suppl 1):S13-S24. (2) Tran PV et al. Dual monoamine modulation for improved treatment of major depressive disorder. J Clin Psychopharmacology 2003;23: Milnacipran's Tolerance and Safety Conclusions

34 Bisserbe JC. Clinical utility of milnacipran in comparison with other antidepressants. Int Clin Psychopharmacol 2002;17(Suppl 1):S43-S No lethal danger due to voluntary overdose In doses up to 28 times the recommended daily dose no fatal case no cardiac rhythm abnormalities or coma patients restored without sequelae Milnacipran's Tolerance and Safety Safety in overdose

35 Special Patient Profiles

36 Milnacipran and Special Patient Profiles Depression symptoms 104 A quick onset of action on all symptoms of depression (1) Montgomery S. Dual action antidepressants in clinical practice. Drugs 2001;3(1): (2) Costa e Silva JA. The effect of milnacipran on depressive symptoms. Int J Psych Clin Pract 1999;3(Suppl 2):S21-S27. Weeks % improvement Anxiety Sleep Cognitive symptoms Psychomotor retardation Core symptoms

37 Milnacipran and Special Patient Profiles Retarded depression 105 A significantly higher probability of response vs paroxetine in depressed patients with psychomotor retardation Responder rate in depressed patients with a HDRS retardation score > 3 at study entry * p= Paroxetine 20 mg OD Milnacipran 50 mg BID % responders * Bisserbe JC. Clinical utility of milnacipran in comparison with other antidepressants. Int Clin Psychopharmacol 17 (Suppl 1):S43-S50.

38 Milnacipran and Special Patient Profiles Suicidal risk Less suicide attempts and completed suicides 107 Montgomery SA. The place of milnacipran in clinical practice. Int Clin Psychopharmacol 2003;18(Suppl 1):S1-S9. Suicide attempts Completed suicides Patients exposure years (n) [log scale] PlaceboTCAs SSRIsMilnacipran Treatment

39 Milnacipran and Special Patient Profiles Young active patients Little effect on vigilance and cognition No subjective sedation No enhancement of sedative effects of alcohol No effect on a battery of psychomotor tests measuring reaction time, learning and recall tasks, visuospatial memory (up to 100 mg as a single dose) No alteration of ability to drive a car Other benefits : - no weight modification - minimal sexual dysfunction 108 Milnacipran advantages in patients with active lifestyle (1) Montgomery SA. The place of milnacipran in clinical practice. Int Clin Psychopharmacol 2003;18(Suppl 1):S1-S9. (2) Hindmarch I et al. Pharmacodynamics of milnacipran in young and elderly volunteers. Br J Clin Pharmacol 2000;49: (3) Richet F et al. Effects of milnacipran on driving vigilance. Int J Psychiatr Clin Pract 2004 (in press).

40 Milnacipran and Special Patient Profiles Elderly depressed patients 109 Milnacipran advantages in elderly patients Pharmacokinetic parameters not significantly altered in elderly patients (except in case of renal failure) Limited drug interactions Broad-spectrum efficacy across depressive symptoms Favourable safety profile (less sedation, less cardiovascular events…) (1) Lecrubier Y. Milnacipran : the clinical properties of a selective serotonin and noradrenaline reuptake inhibitor (SNRI). Hum Psychopharmacol 1997;12:S127-S134. (2) Montgomery SA. The place of milnacipran in clinical practice. Int Clin Psychopharmacol 2003;18(Suppl 1):S1-S9.

41 Milnacipran and Special Patient Profiles Elderly depressed patients 111 Milnacipran advantages in elderly patients (aged 50 years) Morishita S, Arita S. Comparison of milnacipran and SSRIs, especially in age. Abstr % responding patients at w10 Milnacipran (n=55 ; mg/day) Fluvoxamine (n=42 ; mg/day) Paroxetine (n=62 ; mg/day) 80% 52% 64% Response : reduction in HDRS score of at least 50% A better response to milnacipran than to SSRI

42 Improvement of sleep patterns (despite being non-sedative) Improvement of sleep latency and number of nocturnal awakenings Increase of latency of rapid eye movement (REM) sleep Milnacipran and Special Patient Profiles Depressed patients with sleep disorders 112 (1) Puech A et al. Milnacipran, a new serotonin and noradrenaline reuptake inhibitor : an overview of its antidepressant activity and clinical tolerability. Int Clin Psychopharmacol 1997;12: (2) Poirier MF et al. Double-blind comparative study of the action of repeated administration of milnacipran versus placebo on cognitive functions in healthy volunteers. Hum Psychopharmacol Clin Exp 2004;19:1-7. Improvement of sleep

43 113 Response : reduction in HDRS score of at least 50% Milnacipran and Special Patient Profiles Preferential response to milnacipran Differential effects of Milnacipran and SSRIs Improved response in agitated and inhibited depression % response at w2 Milnacipran (n=55 ; mg/day) Inhibited depression Agitated depression Fluvoxamine (n=42 ; mg/day) Paroxetine (n=55 ; mg/day) Morishita S, Arita S. Differential response of milnacipran and SSRIs for inhibition and agitation. Abstr 2004.

44 114 Milnacipran and Special Patient Profiles Switch to mania Less switch to mania or hypomania than with SSRIs Morishita S, Arita S. Prevalence of switch mania in patients with milnacipran or SSRIs. Abstr Retrospective cohort analysis of outpatients major depression disorder or bipolar disorder depression % patients with manic change Milnacipran (n=68 ; mg/day) Fluvoxamine (n=122 ; mg/day) Paroxetine (n=79 ; mg/day) 1.47% 4.90% 8.86%

45 Rouillon F et al. Prevention of recurrent depressive episodes with milnacipran : consequences on quality of life. J Affect Disord 2000;58: Milnacipran's place in major depression A better quality of life 120 A tremendous improvement of quality of life Over 63% improvement % score improvement in DIP* score month 6 vs baseline % 72.0% 80.5% 72.4% 69.7% 62.2% 70.5% 62.2% 68.1% 69.0% * DIP : Disability and Impact Profile, a quality of life questionnaire Sleep Emotional Home assistance Mobility SocialAlertness Communication Recreation Psycho-social score Total score

46 In other pathologies

47 Milnacipran in other pathologies Anxiety Disorders => Generalised Anxiety Disorder (GAD) => Panic Disorder (PD) => Fibromyalgia (FMS) => Social Anxiety Disorder (Social Phobia) => Post-Traumatic Stress Disorder (PTSD) 122

48 Tsukamoto T et al. Usefulness of milnacipran in the treatment of Generalized Anxiety Disorder. Abstr Milnacipran in other pathologies Anxiety Disorders Generalised Anxiety Disorder Weeks HAM-A Total score Milnacipran 45–150 mg/day Open study

49 Nagata T et al. Open trial of milnacipran for Taijin-Kyofusho in Japanese patients with Social Anxiety Disorder. Int J Psych Clin Pract 2003;00:1-6. Milnacipran in other pathologies Anxiety Disorders Social Phobia 124 Open trial (n=12) in patients with Taijin-Kyofusho (DSM-IV Social Phobia criteria) Milnacipran 50–150 mg/day 0 48 Weeks 12 LSAS (Liebowitz Scale) score p<0.001

50 Five outpatients suffering from chronic pain since 17.8 months (mean) treated with milnacipran mg/day for 12 weeks. Kamata M et al. Efficacy of milnacipran for the treatment of chronic pain patients. Abstr Endpoint (w12) VAS pain score Baseline Milnacipran in other pathologies Chronic Pain Chronic abdominal, back, chest and glossal pain A significant improvement in pain

51 Tanikawa H. Efficacy or milnacipran in patients with chronic orthopedic pain including degenerative spondylosis. Abstr Milnacipran in other pathologies Chronic Pain Chronic orthopaedic pain (including degenerative spondylosis) 126 Open trial (n=17) in patients suffering from pain in the trunk and/or extremities due to degenerative spondylosis A significant improvement in pain Weeks Pain VAS Milnacipran mg BID

52 Results of a US phase II double-blind placebo-controlled trial Milnacipran vs Placebo (4 weeks dose escalation + 8 weeks fixed dose) ; 84% of patients at 200 mg/day Cypress Bioscience Inc (www.cypressbio.com). Milnacipran in other pathologies Chronic Pain Fibromyalgia (FMS) - related pain 127 A significant improvement in pain * p= ** p=0.004 % patients Placebo Milnacipran > 50% reduction in pain intensity 14% 37%* Improvement 38% 75%**

53 Patients (n=11) with no significant depressive symptomatology at endpoint Open-label trial, patients with fibromyalgia and a depressive state score of 50 on the Zung Self-rating Depression Scale; milnacipran dose-escaladation up to 100 mg/day for 12 weeks. Nagaoka S et al. An open-label clinical trial of milnacipran in fibromyalgia syndrome with co-morbid depressive symptoms. Int J Psych Clin Pract 2003;1-5. Milnacipran in other pathologies Chronic Pain Fibromyalgia (FMS) - related pain in patients with depressive symptoms 128 A significant improvement in pain associated with relief from depressive symptomatology p<0.01 VAS pain score Baseline Endpoint (w12)

54 Nakanishi S et al. Efficacy of milnacipran for depressive symptoms in schizophrenia spectrum disorders. Psychiatry Clin Neurosci 2004;58(2): Milnacipran in other pathologies Depression in schizophrenia spectrum disorders Schizophrenia, delusional and schizoaffective disorders with depressive symptoms 129 A significant improvement of depressive symptomatology *Self-rating Depression Scale Open-label study, milnacipran up to mg/day p=0.008 Baseline Endpoint (w8) 58.3 ± SDS* Score 42.4 ±9.6

55 How to prescribe

56 How to prescribe milnacipran Dosing schedule 131 It is advisable to start with a low dose of 25 mg twice daily or 50 mg once daily of milnacipran The dose should then be progressively increased to 100 mg/day Recommended (optimum) dosage : 100 mg a day in two 50 mg doses, 1 capsule morning and evening Doses up to 200 mg/day can be safely given where further efficacy is required Milnacipran can be taken with food (food does not modify the pharmacokinetics of milnacipran ; nevertheless, less nausea is observed when administered with food, and it is recommended that milnacipran be taken during meals)

57 איקסל נמצא בקופות החולים: השתתפות המטופל מכבי - 50% מאוחדת - 15% השתתפות המטופל לאומית - 60% השתתפות המטופל מחיר שוק פרטי לחודש טיפול במינון של 100 מ"ג ליום


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