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Pharmacologic Treatments Center for the Advancement of Women’s Health University of Kentucky First-things first: Treat nonfibromyalgia conditions • Arthritis, bursitis, tendonitis – Anti-inflammatory drugs, injections • Migraine headaches – Triptans (e.g. Imitrex, Maxalt, others) • Temporomandibular disorder – Bite blocks • Irritable bowel – Motility agents, antispasmodics (e.g. Zelnorm) • Restless legs – Dopamine agonists (e.g. Mirapex) • Sleep apnea – CPAP • Thyroid problems • Depression Things to remember • We are treating central pain • The best results include drug and nondrug treatments together • There is no drug that cures fibromyalgia – Our goal is to manage the symptoms and improve function and quality of life • Some drugs that may work have not been studied, so there is no data on which to base conclusions Treat fibromyalgia • “Antidepressants” – Drugs that increase concentrations of norepinephrine, serotonin, or both – Called “antidepressants”, but work on many brain and spinal cord pathways – Increase descending pain inhibitory pathways – Can affect other symptoms, e.g. sleep or mood Classes of “antidepressants” • Tricyclic antidepressants (TCA) – Amitryptiline (Elavil), nortryptiline (Pamelor), doxepine (Sinequan), and others • TCA-related – Cyclobenzaprine (Flexeril) • Selective serotonin reuptake inhibitors (SSRI) – Fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa), and others • Serotonin-norepinephrine reuptake inhibitors (SNRI) – Venlafaxine (Effexor), duloxetine (Cymbalta) • Others – trazodone (Desyrel),buproprion (Wellbutrin) Relative Serotonin and Norepinephrine Reuptake Among Antidepressants Serotonin Citalopram Fluvoxamine Sertraline Paroxetine Fluoxetine Mixed Venlafaxine Norepinephrine Amitriptyline Duloxetine Milnacipran Imipramine Maprotiline Desipramine Nortriptyline Reboxitine How do you start? • Usually start with drugs that have “been around” – Minimize unexpected side effects – Longer time to be sure there are no unexpected side effects • Use drugs according to symptoms – TCA useful for sleep AND pain – SSRI may help with energy – Can use combinations What about the drugs really tested in fibromyalgia? • Amitryptiline – Works in 30-50% of patients to reduce symptoms about 30-50% in studies – In practice, works a bit better if used early and if no side effects • Dry eyes and mouth, rapid heart beat (do not use if heart disease), somnolence • Cyclobenzaprine – A little less potent, but fewer side effects – Good place to start! What about the drugs really tested in fibromyalgia? • Citalopram – Doesn’t work very well (as a single agent) for pain • Fluoxetine – Can be used at lower doses for depressive symptoms – May need higher doses to improve pain • Venlafaxine – Same as above Duloxetine • Balanced and potent serotonin and norepinephrine reuptake inhibitor • Approved for the treatment of major depressive disorder in adults and diabetic peripheral neuropathy • Duloxetine (DLX) also reduced painful physical symptoms associated with depression • DLX has been studied, but not approved, for the treatment of FM Arnold LM et al. Arthritis Rheum. 2004;50:2974-2984. This information concerns a use that has not been approved by the US Food and Drug Administration. BPI Average Pain Severity Mean Change from Baseline 0 1 2 4 6 8 10 12 LS Mean Change from Baseline BPI Average Pain 0.0 -0.5 *P < .05 vs placebo. **P < .01 vs placebo. ***P < .001 vs placebo. BPI = Brief Pain Inventory. -1.0 -1.5 -2.0 -2.5 -3.0 -3.5 *** *** *** *** Placebo DLX 60 mg q.d. DLX 60 mg b.i.d. *** * * *** *** *** *** Study 2 *** *** *** Arnold LM et al. Arthritis Rheum. 2004;50:2974-2984; Wernicke JF et al. Presented at: 68th Annual Scientific Meeting of the American College of Rheumatology; October 16-21, 2004; San Antonio, Tex. This information concerns a use that has not been approved by the US Food and Drug Administration. Patients (%) Treatment-Emergent Adverse Events Statistically Significant from Placebo 30 Placebo (n = 103) 25 DLX 60 mg b.i.d. (n = 104) * 20 *** 15 * 10 5 * 0 Anxiety Constipation Dry Mouth Insomnia *P < .05 vs placebo; ***P < .001 vs placebo. The treatment-emergent adverse events were generally mild to moderate in severity. Arnold LM et al. Arthritis Rheum. 2004;50:2974-2984. This information concerns a use that has not been approved by the US Food and Drug Administration. Summary of Studies of TCA, SSRI, and SNRI for Treatment of FMS • Inhibition of both serotonin and norepinephrine gives optimal results • Moderate overall efficacy • For TCA, improvement may be attributed to the sedative effects • Low doses TCA useful, e.g. cyclobenzaprine 10-30 mg or amitriptyline 10-50 mg • Higher doses may be required for efficacy of SSRI and SNRI • No study identified predictors of response Arnold LM et al. Psychosomatics. 2000;41:104-113. This information concerns a use that has not been approved by the US Food and Drug Administration. 2 Ligands • Drugs that block neuronal excitability – Called “anticonvulsants,” but many other actions – Gabapentin/Neurontin and pregabalin/Lyrica • Pregabalin indicated for neuropathic pain – Diabetic peripheral neuropathy – Postherpetic neuralgia • Pregabalin effective for spinal cord injury and FMS • Pregabalin relieves generalized anxiety disorder, but not approved • Pregabalin indicated as add-on for epilepsy Pregabalin • Binds to 2 subunit of voltage-gated calcium channels of neurons • Reduces calcium influx at nerve terminals and therefore inhibits release of neurotransmitters – Glutamate, substance P Pregabalin Crofford LJ et al. Arthritis Rheum. 2005;52:1264-1273. Proportion of Responders Proportion of Responders (%) 35 28.9%*** 30 25 18.9% 20 15 13.2% 13% 10 5 0 Placebo 150 300 Pregabalin Dose (mg/d) 450 • A significantly larger proportion of patients receiving pregabalin 450 mg/day experienced pain relief (defined by a ≥ 50% reduction in pain from baseline to endpoint) compared with those receiving placebo ***P = .003 vs placebo. Crofford LJ et al. Arthritis Rheum. 2005;52:1264-1273. This information concerns a use that has not been approved by the US Food and Drug Administration. Most Common Adverse Events1 Pregabalin Adverse Event Placebo (n = 131) No. (%) 150 mg/d (n = 132) No. (%) 300 mg/d (n = 134) No. (%) 450 mg/d (n = 132) No. (%) Dizziness 14 (10.7) 30 (22.7) 42 (31.3) 65 (49.2) 6 (4.6) 21 (15.9) 37 (27.6) 37 (28.0) Headache 25 (19.1) 16 (12.1) 20 (14.9) 17 (12.9) Dry mouth 2 (1.5) 9 (6.8) 8 (6.0) 17 (12.9) Peripheral edema 1 (0.8) 7 (5.3) 9 (6.7) 14 (10.6) 22 (16.8) 11 (8.3) 13 (9.7) 13 (9.8) Somnolence Infection • Withdrawal rate for dizziness in PGB 450-mg group: 3.8% • Withdrawal rate for somnolence in PGB 450-mg group: 2.3% 1. AEs occurring ≥ 10% in any treatment group. Crofford LJ et al. Arthritis Rheum. 2005;52:1264-1273. Drugs for sleep • Don’t use drugs until you have optimized sleep hygiene • Generally prefer to use drugs that treat other symptoms in addition to sleep first – TCA • Most other sleep drugs can cause dependence and don’t necessary improve sleep quality – If you don’t use them all the time, they work more consistently when you really need them • Treat primary sleep disorders – Restless leg syndrome – Sleep apnea Drugs for pain • Drugs used for “normal” pain (anti-inflammatory drugs, e.g. ibuprofen, naproxen) don’t work well for “central” pain • Narcotic drugs cause problems it is better to avoid – – – – – Cognitive problems Fatigue Changes in the spinal cord that actually worsen pain Dependence/withdrawal Social stigma • If you feel you must use these drugs, know what your goal is … – Don’t treat to absence of pain – Treat to improved function • Able to work • Able to exercise Complementary and alternative treatments (CAM) Conventional Medicine Bottom Up Widespread Use Research VS Complementary Medicine Top Down Widespread Use Research Yet Common Goals Management of symptoms (pain, fatigue, poor sleep etc.) Enhancement of cognitive and physical function Why do people choose CAM? • Frustration: alternatives are often sought when there are no clearly effective conventional options. • Personal Choice: people often chose complementary therapies because they want to play an active role in their healing and because they prefer a “natural” approach – Be aware that most “natural” products are manufacture – CAM products are not regulated by the FDA Unstudied Alternative Therapies • If it sounds too good to be true, it probably is … It doesn’t have to be true to say/write it • If it costs a lot … Beware of quackery • Assess safety! • Use an “n-of-1” trial approach - and apply same standard to all treatments – – – – Record how you feel before you start Try it for a month and record how you feel If you think you are better, stop it for 2 weeks If you are better on drug and worse off drug, then if works for you!