Transcript Pharmacologic Treatments

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!