Download Fibromyalgia

Fibromyalgia:
Fact or Figment?
Mary La, PharmD
Post-Graduate Year 1 Pharmacy Resident
University of Kentucky HealthCare
Wednesday, April 6, 2016
Pre-Class Question #1
• What do you find when you Google-search
“fibromyalgia cure”?
Lecture Objectives
• Describe the risks factors and scoring/assessment
of a patient with fibromyalgia.
• Discuss the clinical presentation of fibromyalgia,
as well as potential differential diagnoses.
• Define the typical management strategies for
fibromyalgia.
What is Fibromyalgia?
• A syndrome characterized by chronic, widespread
pain
• Centralized pain state
• Amplified pain response:
– Allodynia – increased sensitivity to stimuli that are not
normally painful
– Hyperalgesia – increased response to stimuli that are
normally painful
Clauw DJ. JAMA. 2014; 311(15): 1547-1555.
Dymon TE. ACSAP (Neurol Psych Care I) 2015: 5-18.
Epidemiology
•
•
•
•
2-8% of the general population affected
More women than men affected
More older age affected (60-79 yrs)
Complications
– Reduced quality of life
– Decreased functioning and ability to do ADLs
Clauw DJ. JAMA. 2014; 311(15): 1547-1555.
Risk Factors
• Non-modifiable
– Family history
– Environmental factors: infection, trauma, deployment to war,
psychological stress
– May co-occur with other chronic pain conditions (OA, RA, lupus)
• Potentially modifiable
–
–
–
–
Poor sleep
Obesity
Physical inactivity
Poor job/life satisfaction
Clauw DJ. JAMA. 2014; 311(15): 1547-1555.
Pathophysiology
• ↓ CSF levels of NE, 5HT, DA in patients w/ fibromyalgia
• Dysregulation of hypothalamus-pituitary-adrenal axis →
↑ corticotropin-releasing hormone & substance P activity →
↑ proinflammatory & neurosensitizing molecules
Lucas HJ et al. Int J Immunopath Pharmacol. 2006; 19(1): 5-9.
Russell IJ et al. Arthritis Rheum. 1992; 35(5): 550-556.
Diagnosis
• 2011 American College of
Rheumatology diagnostic criteria
Signs and Symptoms
• Amplified pain response:
allodynia, hyperalgesia
• Fatigue
• Sleep disturbance
• Diffuse tenderness
• Mood disturbance
• Cognitive difficulties
– 19 pain locations
– 41 somatic symptoms
– Does not include “tender point
examination”
• Should be suspected in multifocal
pain not entirely explained by injury
or inflammation
• May have history of chronic pain
• May be a diagnosis of exclusion
– Hypothyroidism
– Rheumatic disorders
– Adverse drug effect (statins, opioids)
Clauw DJ. JAMA. 2014; 311(15): 1547-1555.
Scoring & Assessment
• Widespread Pain Index (WPI) and Symptom Severity
(SS) scale
– WPI ≥ 7 and SS ≥ 5
– WPI 3-6 and SSI ≥ 9
•
•
•
•
Fibromyalgia Diagnostic Screen
Fibromyalgia Impact Questionnaire
Brief Pain Inventory (BPI)
Medical Outcomes Study 36-Item Short-Form Health
Survey (SF-36)
Clauw DJ. JAMA. 2014; 311(15): 1547-1555.
Management
Goals of therapy: Improvement of function, reduction of pain
symptoms
Gabapentinoids
Non-pharmacologic
Pharmacologic
Serotoninnorepinephrine
reuptake inhibitors
(SNRIs)
Tricyclic
Antidepressants
(TCAs)
Clauw DJ. JAMA. 2014; 311(15): 1547-1555.
Skeletal Muscle
Relaxants
Dopamine Agonists
Pharmacologic and NonPharmacologic Approaches
• Improved global impression of change in
fibromyalgia
– “Being employed”
– “Full participation in a program”
• Worse impression of overall health
– Longer duration of FM symptoms
– More limitations in physical functioning
Van Eijk-Hustings Y et al. Clin Rheumatol. 2015; 34(1): 133-141.
Pharmacologic Therapies
• Gabapentinoids
• Skeletal muscle
relaxants
• SNRIs
• TCAs
• Dopamine
agonists
Pharmacologic Therapies
Clauw DJ. JAMA. 2014; 311(15): 1547-1555.
Dymon TE. ACSAP (Neurol Psych Care I) 2015: 5-18.
General Principles
• Doses for pain syndromes < doses for depression/anxiety…
– …but may have to be dosed to effect and tolerance
• Agents in the same therapeutic class may not share the
same PK/PD, degree of therapeutic effect at comparable
doses, etc.
• The antidepressants (e.g. SNRIs, TCAs) have black box
warnings for suicidal thoughts and behaviors
– Close monitoring for unusual changes in behavior, suicidality, or
clinical worsening is warranted
Gabapentinoids
Examples
Dose Ranges
Gabapentin, pregabalin
Gabapentin: 800 mg – 2400 mg/day
Pregabalin: 150 mg – 450 mg/day
Mechanism of
Action
• Binding sites associated w/ presynaptic voltage-gated Ca channels
which may modulate excitatory neurotransmitter release involved in
nociception
• Pregabalin: May also modulate pain pathway signaling between
brainstem and spinal cord
Adverse Effects
Dizziness, ↑ weight, sedation
Interactions
CNS depressants
Dose
Adjustments
Renal adjustment
Comments
• Can help with pain and sleep
• Also used for seizures, post-herpetic neuralgia, diabetic neuropathy
Dymon TE. ACSAP (Neurol Psych Care I) 2015: 5-18.
Lexi-Drugs. 2016.
Micromedex. 2016.
Serotonin-Norepinephrine Reuptake
Inhibitors (SNRIs)
Examples
Duloxetine, venlafaxine, milnacipran
Dose Ranges
Duloxetine: 30-60 mg/day
Venlafaxine: 37.5 mg – 375 mg/day
Milnacipran: 12.5 mg – 100 mg/day
Mechanism of
Action
Inhibits reuptake of synaptic 5HT and NE back into neurons
Adverse Effects
↑ BP, ↑ HR, nausea, sweats, headache, dry mouth
Interactions
MAOIs and other serotonergic agents; duloxetine is a CYP1A2 substrate;
venlafaxine is a CYP3A4 and 2D6 substrate; dulox/venlaf are CYP2D6
inhibitors
Dose
Adjustments
Renal adjustment; hepatic adjustment (dulox/venlaf)
Comments
• Also used in depression, anxiety, diabetic neuropathy
• Venlafaxine may require higher doses (closer to depression-indicated
dose ranges) to see 5HT3 and NE effects
Clauw DJ et al. Clin Ther. 2008; 30(11): 1988-2004.
Dymon TE. ACSAP (Neurol Psych Care I) 2015: 5-18.
Lexi-Drugs. 2016. | Micromedex. 2016.
Tricyclic Antidepressants (TCAs)
Examples
Amitriptyline, nortriptyline
Dose Ranges
Amitriptyline: 25-50 mg/day
Nortriptyline: 12.5-25 mg/day
Mechanism of
Action
5HT and NE reuptake inhibition
Adverse Effects
Dry mouth, ↑ weight, somnolence, GI disturbances, ↑ QTc
Interactions
• Anticholinergic agents, MAOIs and other serotonergic agents, QTc
prolonging agents
• Amitriptyline and nortriptyline are CYP2D6 substrates
Dose
Adjustments
No specific renal or hepatic recommendations given
Comments
• Can help with pain, sleep, and fatigue
• Also used in depression, diabetic neuropathy, and migraine
prophylaxis
Dymon TE. ACSAP (Neurol Psych Care I) 2015: 5-18.
Lexi-Drugs. 2016.
Micromedex. 2016.
Smith B et al. Drug Class Review: Drugs for Fibromyalgia. 2011.
Skeletal Muscle Relaxants
Amitriptyline
Cyclobenzaprine
Carisoprodol
Tizanidine
Metaxalone
ChemSpider. 2016.
Skeletal Muscle Relaxants (cont.)
Examples
Dose Ranges
Cyclobenzaprine
10 mg – 30 mg/day
Mechanism of
Action
Acts at level of brainstem to modulate tonic somatic motor activity
Adverse Effects
Drowsiness, dizziness, dry mouth, constipation, ↑ HR
Interactions
• MAOIs and other serotonergic agents
• CYP1A2 substrate
Dose
Adjustments
Hepatic adjustment
Comments
• Can help with pain and sleep symptoms, not as much with fatigue or
tender points
Dymon TE. ACSAP (Neurol Psych Care I) 2015: 5-18.
Flexeril. [Package Insert] Titusville, NJ: McNeil; 2013.
Lexi-Drugs. 2016.
Micromedex. 2016.
Dopamine Agonists
Examples
Dose Ranges
Pramipexole, ropinirole
Pramipexole: 0.25 mg – 4.5 mg/day
Ropinirole: 0.25 mg – 24 mg/day
Mechanism of
Action
Agonist at DA receptors (D2, D3); may help module excessive adrenergic
arousal (which lead to negative effects on sleep in fibromyalgia)
Adverse Effects
Orthostatic hypotension, drowsiness, dizziness, impulse control,
extrapyramidal symptoms
Interactions
• Antipsychotics
• Ropinirole: CYP1A2 substrate
Dose
Adjustments
Renal adjustment
Comments
• Can help with pain and fatigue symptoms
Dymon TE. ACSAP (Neurol Psych Care I) 2015: 5-18.
Holman AJ et al. Arth Rheum. 2005; 52(8): 2495-2505.
Lexi-Drugs. 2016.
Micromedex. 2016.
Pre-Class Question #2
• What are some of the challenges with studying
the effect of proposed interventions in
fibromyalgia?
Role of Anti-Psychotics?
• Single-center, open-label, non-inferiority trial
• Arms:
– Quetiapine XR (50-300 mg PO daily) – target 100
mg/day
– Amitriptyline (10-75 mg PO daily) – target 25 mg/day
• Duration of therapy: 16 weeks
Calandre et al. Psychopharmacology. 2014; 231: 2525-2531.
Role of Anti-Psychotics? (cont.)
• Included:
– Age 18-70 yrs meeting diagnostic criteria for fibromyalgia
• Excluded:
–
–
–
–
–
Axis I psychiatric condition other than major depression
Severe depression
Substance/EtOH abuse
Serious physical illness
Received quetiapine or amitriptyline w/in 1 year of starting
study
• Primary outcome:
– Change from baseline to endpoint in FM Impact Questionnaire
(FIQ)
Calandre et al. Psychopharmacology. 2014; 231: 2525-2531.
Role of Anti-Psychotics? (cont.)
• Randomized 90 patients, though only 56 patients
completed the study
• Most were:
– Age ~50 yrs
– Female
– ~4 yrs out from diagnosis
• No significant differences found in FIQ scores
between study arms
• More adverse effects leading to study withdrawal
observed in the quetiapine arm (14/23 withdrawals)
over the amitriptyline arm (3/11 withdrawals)
Calandre et al. Psychopharmacology. 2014; 231: 2525-2531.
Therapies under Evaluation
• Low-dose naltrexone
• Transcutaneous electrical nerve stimulation
(TENS)
• Cannabinoids
Pre-Class Question #3
• What are some reputable sources of information
on fibromyalgia?
– American College of Rheumatology – Fibromyalgia
– National Institute of Arthritis and Musculoskeletal and
Skin Diseases – Fibromyalgia
– PubMed
Summary
• Signs and symptoms of fibromyalgia include amplified
pain response as well as mood and cognitive
disturbances.
• Risk factors include family/environmental factors, as
well as physical inactivity and a history of chronic
pain.
• The pharmacologic mainstays of therapy include
gabapentinoids, SNRIs, and/or TCAs, though the
optimal approach also combines non-pharmacologic
therapies.
Fibromyalgia:
Fact or Figment?
Mary La, PharmD
Post-Graduate Year 1 Pharmacy Resident
University of Kentucky HealthCare
Wednesday, April 6, 2016
Email: [email protected]