dr liu fibromyalgia disease overview-1
TRANSCRIPT
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Fibromyalgia: A Chronic Widespread Fibromyalgia: A Chronic Widespread
Neurologic Pain ConditionNeurologic Pain Condition
Disease Overview and DiagnosisDisease Overview and Diagnosis
Hongbiao (Hank) Liu MD PhDHongbiao (Hank) Liu MD PhD
Luna Medical Care PC -- Mobile MDLuna Medical Care PC -- Mobile MD
656 Elmwood Ave.656 Elmwood Ave.Buffalo NY 14222Buffalo NY 14222
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What is Fibromyalgia?
• Pathogenesis of Fibromyalgia
• Clinical Features and Diagnosis of Fibromyalgia
• Management of Fibromyalgia
• Summary
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Categorization of Pain ConditionsCategorization of Pain Conditions
Courtesy of Woolf C. Ann Intern Med. 2004;140:441-451.
Chronic PainChronic PainAcute PainAcute Pain
Central Pain Central Pain AmplificationAmplificationCentral Pain Central Pain AmplificationAmplification
Abnormal pain Abnormal pain processing by CNSprocessing by CNS
(ie, Fibromyalgia)(ie, Fibromyalgia)
Nociceptive PainNociceptive PainNociceptive PainNociceptive Pain
Noxious stimuliNoxious stimuli
(ie, Burn)(ie, Burn)
Inflammatory PainInflammatory PainInflammatory PainInflammatory Pain
InflammationInflammation
(ie, Rheumatoid arthritis)(ie, Rheumatoid arthritis)
Neuropathic PainNeuropathic PainNeuropathic PainNeuropathic Pain
Neuronal damageNeuronal damage
(ie, Herpes zoster)(ie, Herpes zoster)
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Fibromyalgia (FM): A Chronic Fibromyalgia (FM): A Chronic Widespread Neurologic Pain ConditionWidespread Neurologic Pain Condition
FM is a neurological condition associated with chronic widespread pain (CWP) and tenderness1
American College of Rheumatology (ACR) criteria for the diagnosis of FM:2
– Chronic widespread pain
• Pain for ≥3 months
• Pain above and below the waist
• Pain on left and right sides of body and axial skeleton
– Pain at ≥11 of 18 tender points when palpated with 4 kg of digital pressure
1. Wolfe F, et al. Arthritis Rheum. 1995;38(1):19-28.2. Wolfe F, et al. Arthritis Rheum. 1990;33:160-172.
Diagram showing 18 tender points
ACR criteria are both sensitive ACR criteria are both sensitive (88.4%) and specific (81.1%)(88.4%) and specific (81.1%)22
ACR criteria are both sensitive ACR criteria are both sensitive (88.4%) and specific (81.1%)(88.4%) and specific (81.1%)22
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Epidemiology of FMEpidemiology of FM
FM is one of the most common CWP conditionsFM is one of the most common CWP conditions11
Prevalence in United States is estimated to be 2%-5%Prevalence in United States is estimated to be 2%-5%
of the adult populationof the adult population11Prevalence in United States is estimated to be 2%-5%Prevalence in United States is estimated to be 2%-5%
of the adult populationof the adult population11
Impacts a wide range of patientsImpacts a wide range of patients22
• Most patients are between 25 and 60 years of age• Women more likely to be diagnosed than men
Impacts a wide range of patientsImpacts a wide range of patients22
• Most patients are between 25 and 60 years of age• Women more likely to be diagnosed than men
FM is highly underdiagnosedFM is highly underdiagnosed22
• Only 1 in 5 is diagnosedOnly 1 in 5 is diagnosed• Diagnosis takes an average of 5 yearsDiagnosis takes an average of 5 years33
FM is highly underdiagnosedFM is highly underdiagnosed22
• Only 1 in 5 is diagnosedOnly 1 in 5 is diagnosed• Diagnosis takes an average of 5 yearsDiagnosis takes an average of 5 years33
1. Wolfe F, et al. Arthritis Rheum. 1995;38:19-28.2. Weir PT, et al. J Clin Rheumatol. 2006;12:124-128.3. National Pain Foundation. Available at: http://nationalpainfoundation.org/articles/849/facts-and-statistics. Accessed July 21, 2009.
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Risk Factors for FMRisk Factors for FM
Genetic factors1
– Relatives of FM patients are at higher risk for FM• First-degree relatives are significantly more likely to have
FM (Odds ratio=8.5; P =0.0002)• Have significantly more tender points
Environmental factors2
– Physical trauma or injury– Infections (Lyme disease, hepatitis C)– Other stressors (eg, work, family, life-changing events)
Gender3
– Women are diagnosed with FM about 7 times as often as men
1. Arnold LM, et al. Arthritis Rheum. 2004;50(3):944-952.2. Mease PJ. J Rheumatol. 2005;32(suppl 75):6-21. 3. Arnold LM, et al. Arthritis Rheum. 2004;50(9):2974-2984.
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• What is Fibromyalgia?
Pathogenesis of Fibromyalgia
• Clinical Features and Diagnosis of Fibromyalgia
• Management of Fibromyalgia
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The Normal Pain Processing PathwayThe Normal Pain Processing Pathway
3. A signal is sent via the ascendingascending tract to the brain, and perceived as pain
2. Impulses from afferents depolarize dorsal horn neurons, then, extracellular Ca2+ diffuse into neurons causing the release of Pain Associated Neurotransmitters – GlutamateGlutamate and Substance PSubstance P
1. Stimulus sensed by the peripheral nerve (ie, skin)
1. Staud R and Rodriguez ME. Nat Clin Pract Rheumatol. 2006;2:90-98.
2. Gottschalk A and Smith DS. Am Fam Physician. 2001;63:1979-1984.
4. The descendingdescending tract carries modulating impulses back to the dorsal horn
Pain Pain PerceivedPerceived
Glutamate
Substance P
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Central Sensitization: A Theory for Central Sensitization: A Theory for Neurological Pain Amplification in FMNeurological Pain Amplification in FM
Central sensitization is believed to be an underlying cause of the amplified pain perception that results from dysfunction in the CNS1 – May explain hallmark features of generalized heightened pain sensitivity2
• Hyperalgesia – Amplified response to painful stimuli • Allodynia - Pain resulting from normal stimuli
Theory of central sensitization is supported by:– Increased levels of pain neurotransmitters3,4
• Glutamate • Substance P
fMRI data demonstrates low intensity stimuli in patients with FM comparable to high intensity stimuli in controls5
fMRI = functional magnetic resonance imaging
1. Staud R and Rodriguez ME. Nat Clin Pract Rheumatol. 2006;2:90-98. 2. Williams DA and Clauw DJ. J Pain. 2009;10(8):777-791. 3. Sarchielli P, et al. J Pain. 2007;8:737-745.4. Vaerøy H, et al. Pain. 1988;32:21-26.5. Gracely RH, et al. Arthritis Rheum. 2002;46:1333-1343.
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Central Sensitization Produces Abnormal Central Sensitization Produces Abnormal Pain SignalingPain Signaling
After nerve injury, increased input to the dorsal horn can induce central sensitizationPerceived pain
Ascendinginput
Descendingmodulation
Nerve dysfunction
Nociceptive afferent fiber
Minimalstimuli
Perceived pain(hyperalgesia/allodynia)
Induction of central sensitization
Increased release of pain neurotransmitters glutamate and substance P
Pain amplification
1. Adapted from Gottschalk A and Smith DS. Am Fam Physician. 2001;63:1979-1984. 2. Woolf CJ. Ann Intern Med. 2004;140:441-451.
Increased pain perceptionIncreased pain perception
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FM: An Amplified Pain ResponseFM: An Amplified Pain Response
Pain Pain amplificationamplification
responseresponse
Su
bje
ctiv
e p
ain
in
ten
sity
Su
bje
ctiv
e p
ain
in
ten
sity
Stimulus intensityStimulus intensity
Normal painNormal painresponseresponse
(when a pinprick causes an intense stabbing sensation)
Hyperalgesia
10
8
6
4
2
0
Adapted from Gottschalk A and Smith DS. Am Fam Physician. 2001;63:1979-1986.
Allodynia(hugs that feel painful)
Pain in FMPain in FM
12Gracely RH, et al. Arthritis Rheum. 2002;46:1333-1343.
fMRI Study Supports the Amplification of fMRI Study Supports the Amplification of Normal Pain Response in Patients With FMNormal Pain Response in Patients With FM
14
12
10
8
6
4
2
0
4.51.5 2.5 3.5
Stimulus intensity (kg/cm2)
Pai
n i
nte
ns
ity
FM (n=16)Subjective pain controlStimulus pressure control
(n=16)
Patients with FM experienced high pain with low grade stimuli
Yellow: Area of overlap (ie, area activated at high intensity stimuli in control patients was activated by low intensity stimuli in patients with FM)
Green: Activated only at high intensity stimulus in controls
Red: Activation at low intensity stimulus in patients with FM
fMRI = functional magnetic resonance imaging
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Patients With FM Have Elevated Pain Patients With FM Have Elevated Pain Neurotransmitter Substance P in Their CSFNeurotransmitter Substance P in Their CSF
0
10
20
30
40
50
Russell 1994 Russell 1995 Bradley
FM patients
Healthy control subjects
1. Russell IJ, et al. Arthritis Rheum. 1994;37:1593-1601. 2. Russell IJ, et al. Myopain 1995: Abstracts from the 3rd World Congress on Myofascial Pain and Fibromyalgia; July 30 - August 3, 1995; San Antonio, TX.3. Bradley LA, et al. Arthritis Rheum. 1996;suppl 9:212. Abstract 1109.
n=32 n=24 n=14 n=32 n=24 n=14
Su
bs
tan
ce
P c
on
cen
trat
ion
(f
mo
les/
mL
)†
n=30 n=24 n=10 n=30 n=24 n=10
16.316.3
42.842.8 4343
171712.8312.83
19.2619.26
P<0.001 P<0.001
P<0.03
* 1 * 2 * 3
*CSF sample collected via lumbar puncture in FM and healthy controls and SP levels assessed by radioimmunoassay †fmoles/mL = femtomole/mL = 10-15 mole/mL
In 3 separate clinical studies, substance P, a pain In 3 separate clinical studies, substance P, a pain neurotransmitter, was elevated in FM patientsneurotransmitter, was elevated in FM patients1-31-3
CSF = cerebrospinal fluid
14
0
0.5
1.0
1.5
2.0
2.5
FM patient Control
FM patient
Control
Patients With FM Have Elevated Pain Patients With FM Have Elevated Pain Neurotransmitter Glutamate in Their CSFNeurotransmitter Glutamate in Their CSF
Sarchielli et al measured CSF levels of glutamate in 20 FM patients and 20 age-matched controls
Significantly higher levels of glutamate were found in FM patients compared with controls
Sarchielli P, et al. J Pain. 2007;8:737-745.
PP<0.003<0.003
CS
F le
vel o
f g
luta
mat
e (µ
g/m
L)
CSF Levels of Glutamate
CSF = cerebrospinal fluid
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FM Pathophysiology: Summary FM Pathophysiology: Summary Central sensitization is a leading theory of FM pathophysiology1
Elevated pain neurotransmitters in CSF of patients with FM2-4
– Several studies showed elevated levels of glutamate and substance P
– Elevated levels suggest that this may contribute to pain amplification
fMRI data supports FM as a disorder of central pain amplification5
– Areas activated by high intensity stimuli in control patients were activated by low intensity stimuli in patients with FM
1. Staud R and Rodriguez ME. Nat Clin Pract Rheum. 2006;2:90-98. 2. Russell IJ, et al. Arthritis Rheum. 1994;37:1593-1601.
CSF = cerebrospinal fluidfMRI = functional magnetic resonance imaging 3. Bradley LA, et al. Arthritis Rheum. 1996;suppl 9:212. Abstract 1109.
4. Sarchielli P, et al. J Pain. 2007;8:737-745.5. Gracely RH, et al. Arthritis Rheum. 2002;46:1333-1343.
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• What is Fibromyalgia?
• Pathogenesis of FibromyalgiaClinical Features and Diagnosis of Fibromyalgia
• Management of Fibromyalgia
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1. Leavitt F, et al. Arthritis Rheum. 1986;29:775-781. 2. Wolfe F, et al. Arthritis Rheum. 1995;38:19-28.3. Roizenblatt S, et al. Arthritis Rheum. 2001;44:222-230.
4. Staud R. Arthritis Res Ther. 2006;8(3):208-214.5. Harding SM. Am J Med Sci. 1998;315:367-376.
Chronic Widespread PainChronic Widespread Pain1,21,2
• CORE criteria of FMCORE criteria of FM• Pain is in all 4 quadrants of the body ≥3 monthsPain is in all 4 quadrants of the body ≥3 months
• Patient descriptors of pain include:Patient descriptors of pain include:44
• Aching, exhausting, nagging, and hurtingAching, exhausting, nagging, and hurting
TendernessTenderness22
• Sensitivity to pressure stimuliSensitivity to pressure stimuli• Hugs, handshakes are painfulHugs, handshakes are painful• Tender point exam given to assess tendernessTender point exam given to assess tenderness
• Hallmark features of FMHallmark features of FM44
• HyperalgesiaHyperalgesia• AllodyniaAllodynia
Other SymptomsOther Symptoms2,3,52,3,5
• FatigueFatigue• Pain-related conditions/symptomsPain-related conditions/symptoms
• Chronic headaches/migraines, IBC, IC, TMJ, PMSChronic headaches/migraines, IBC, IC, TMJ, PMS• Subjective morning stiffnessSubjective morning stiffness
• Neurologic symptomsNeurologic symptoms• Nondermatomal paresthesiasNondermatomal paresthesias• Subjective numbness, tingling in extremitiesSubjective numbness, tingling in extremities
• Sleep disturbance Sleep disturbance • Non-restorative sleep, RLSNon-restorative sleep, RLS
Clinical Features of FMClinical Features of FM
Other Other SymptomsSymptoms
18
69
24
4651
98
7279
85
0
20
40
60
80
100
Widespread pain Thoracic pain Lumbar pain Cervical pain
% o
f p
ati
en
ts
Chronic Pain Controls
FM patients
Widespread Pain and Tenderness Widespread Pain and Tenderness are the Defining Features of FMare the Defining Features of FM
Wolfe F, et al. Arthritis Rheum. 1990;33:160-172.
****
**
**
In patients with FM, pain involves more areas In patients with FM, pain involves more areas than other chronic pain conditions than other chronic pain conditions
*P<0.001
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Patients With FM Present With Patients With FM Present With a Global Pain Disordera Global Pain Disorder
While the ACR classification criteria focuses on 18 points, patients do not usually speak of tender points1
This is a pain drawing—a patient colors all areas of the body in which they feel pain2
The diagram shows that the pain of FM is widespread1
1. Wolfe F, et al. Arthritis Rheum. 1990:33:160-172.
2. Silverman SL and Martin SA. In: Wallace DJ, Clauws DJ, eds. Fibromyalgia & Other Central Pain Syndromes. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2005:309-319.
FrontBackAdapted from pain drawing provided courtesy of L Bateman.
ACR = American College of Rheumatology
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ACR-Recommended Manual Tender Point ACR-Recommended Manual Tender Point Survey* for the Diagnosis of FMSurvey* for the Diagnosis of FM
1. Adapted from Chakrabarty S and Zoorob R. Am Fam Physician. 2007;76(2);247-254.
Manual Tender Points SurveyManual Tender Points Survey:: • Presence of 11 tender points on palpation to a maximum of 4 kg Presence of 11 tender points on palpation to a maximum of 4 kg
of pressure (just enough to blanch examiners thumbnail)of pressure (just enough to blanch examiners thumbnail)
OCCIPUT –OCCIPUT – At nuchal muscle At nuchal muscle insertioninsertion
GLUTEAL – GLUTEAL – Upper outer quadrant of Upper outer quadrant of gluteal musclesgluteal muscles
GREATER GREATER TROCHANTER –TROCHANTER – Muscle attachments just Muscle attachments just posterior to GTposterior to GT
SUPRASPINATUS – SUPRASPINATUS – At attachment to medial At attachment to medial border of scapulaborder of scapula
TRAPEZIUS – TRAPEZIUS – Upper border of trapezius, Upper border of trapezius, midportionmidportion
LOW CERVICAL –LOW CERVICAL – Anterior aspects of C5, C7 Anterior aspects of C5, C7 intertransverse spacesintertransverse spaces
SECOND RIB SPACESECOND RIB SPACE –– about 3 cm lateral to sternal about 3 cm lateral to sternal
borderborder
ELBOW – ELBOW – Muscle attachments to Muscle attachments to
Lateral EpicondyleLateral Epicondyle
KNEE – KNEE – Medial fat pad of knee Medial fat pad of knee
proximal to joint lineproximal to joint line
RIGHT FOREARMRIGHT FOREARM
FOREHEADFOREHEAD
LEFT LEFT THUMBTHUMB
Control PointsControl Points
Tender PointsTender Points
*Based on 1990 ACR FM Criteria
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Patients With FM are More Likely to HavePatients With FM are More Likely to HaveConcomitant Chronic Pain ConditionsConcomitant Chronic Pain Conditions
DMBA = Deseret Mutual Benefits Administration SLE = Systemic lupus erythematosus; RA = Rheumatoid Arthritis; IBS = Irritable Bowel Syndrome*Headache = headache, tension headache, migraine†Baseline from 52,698 females and 52,232 males without FM‡Risk ratio = The probability of each condition occurring as compared to a normal, healthy control group (baseline=1)
Associations of pain-related conditions among patients diagnosed Associations of pain-related conditions among patients diagnosed with FM in the DMBA database between 1997 and 2002with FM in the DMBA database between 1997 and 2002
1. Weir PT, et al. J Clin Rheumatology. 2006;12(3):124-128.2. Wolfe F and Rasker JJ. Fibromyalgia. In: Firestein, ed. Kelly’s Textbook of Rheumatology, 8th Edition. St. Louis, MO: WB Saunders Co; 2008.
0
1
2
3
4
5
6
7
SLE RA IBS Headache*
Ris
k ra
tio
Female Male
FM Patients
Female n=906Male n=1689
BaselineBaseline††
• 20% of patients with SLE, RA and OA have concomitant FM20% of patients with SLE, RA and OA have concomitant FM22
• Because patients with FM are often diagnosed with other pain-related conditions, FM may go undetectedBecause patients with FM are often diagnosed with other pain-related conditions, FM may go undetected
‡
22
1. Goldenberg DL, et al. JAMA. 2004;292:2388-2395. 2. Wolfe F, et al. Arthritis Rheum. 1990;33:160-172. 3. Adapted from White KP, et al. Arthritis Rheum. 2002;47:260-265.
Diagnosis of FM Improves Diagnosis of FM Improves Health SatisfactionHealth Satisfaction
3
2.2
0
1
2
3
4Lower number Lower number indicates improved indicates improved patient satisfactionpatient satisfaction
Baseline Post-diagnosis
Pat
ien
t h
ealt
h d
issa
tisf
acti
on
*
*Statistically significant versus baseline (P value not provided) as a change in the 5-point Likert scale
2323
• What is Fibromyalgia?
• Pathogenesis of Fibromyalgia
• Clinical Features and Diagnosis of Fibromyalgia
Summary
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SummarySummary
FM is one of the most common chronic widespread neurologic pain conditions1
– Associated with hyperalgesia and allodynia2 – Central sensitization is a leading theory to explain FM3
– Demonstrated by excessive release of the pain neurotransmitters3 glutamate and substance P
FM is commonly seen with other chronic pain-related conditions4
ACR criteria for the diagnosis of FM are sensitive and specific5
– History of CWP ≥3 months– Pain in 4 quadrants and axial skeleton– ≥11 of 18 tender points
FM diagnosis is a key to successful management6
1. Wolfe F, et al. Arthritis Rheum. 1995;38(1):19-28.2. Gottschalk A and Smith DS. Am Fam Physician. 2001;63:1979-1984.3. Staud R and Rodriguez ME. Nat Clin Pract Rheumatol. 2006;2:90-98.
4. Weir PT, et al. J Clin Rheumatol. 2006;12(3):124-128.5. Wolfe F, et al. Arthritis Rheum. 1990;33:160-172.6. Goldenberg DL, et al. JAMA. 2004;292:2388-2395.
Fibromyalgia TreatmentFibromyalgia Treatment
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IntroductionIntroduction
Fibromyalgia syndrome (FMS)– Common, chronic, widespread pain syndrome– Predominantly middle-aged women
Philosophy of management– Symptom palliation– Functional restoration
Symptoms and co-morbid syndromesSymptoms and co-morbid syndromes
Quantitative abnormalities in pain perception– the form of both allodynia and hyperalgesia
A lot of complaints beyond pain– Table. 1
Symptoms and co-morbid syndromesSymptoms and co-morbid syndromes
Fibromyalgia (FMS) =? Functional somatic syndromes (FSS) Table. 2
FSS includes – Irritable bowel syndrome (IBS)– Chronic low-back pain (CLBP)– Tempomandiblular disordoer (TMD)– Chronic fatigue syndrome (CFS)– Interstitial cystitis (IC)– Multiple chemical sensitivity (MCS)
Irritable bowel syndromeIrritable bowel syndrome
A common disease includes abdominal pain, bloating, and disturbed defecation
The prevalence of IBS is between 8-23% in general population
Three subtypes of IBS are recognized as diarrhea, constipation and discomfort/pain predominant
Chronic low back painChronic low back pain
Up to 70% of adults have at least one episode of back pain during the course of their lifetime
CLBP defines as pain persisting beyond 3 months
Temporomandibular joint Temporomandibular joint disorodersdisoroders
A cluster of common chronic orofacial pain syndromes of unknown etiology
Classified into three groups as myofascial, joint disorder and combined
Chronic tension-type headachesChronic tension-type headaches
CTTH are defined by the presence of bilateral headaches that are mild to moderate in intensity, occurring more than 15 days per month for more than 6 months
Associated symptoms include nausea, photophobia and phonophobia
Psychological distressPsychological distress
Approximately 20-30% of FMS patients have significant current major depressive disorder and about 60% have a lifetime prevalence of depressive illness
Post-traumatic stress disorders and other anxiety disorders may also represent an important cause of psychological distress in fibromyalgia
Treatment strategiesTreatment strategies
Nonpharmacologic and pharmacologic intervention
Aerobic exercise
EMG-biofeedback
Acupuncture
Physical therapy
Cognitive behavioral therapy
Simple analgesiaSimple analgesia
NSAID and acetaminophen
Numerous studies failed to confirm their effectiveness as analgesics in FMS
If co-morbid with OA, RA and SLE, patients can experience enhanced analgesia with combinations of NSAIDs and other agents
Tricyclic antidepressantsTricyclic antidepressants
Most TCAs increase the concentration of 5-HT and NE by directly blocking re-uptake
Additional blockade of certain cation channels as histamine, acetylcholine and NMDA mediated glutamatergic neurotransmission
Poor side effects about anti-histaminergic and anti-acetylcholinergic ability
Tricyclic antidepressantsTricyclic antidepressants
TCAs (Amitriptyline): pain, poor sleep and fatique, but not mood-elevating effects
IBS, TMD and CLBP are treated by TCAs
Dose: from 10mg 1-2h before sleep, and to max dose 50mg/day
Morning “hangover”, sicca symptoms and BW gain
With caution, patients with cardiac disorders esp. arrhythmia
Selective serotonin re-uptake Selective serotonin re-uptake inhibitorsinhibitors
SSRIs primarily inhibit the re-uptake of 5-HT, and they typically lack the extra-monoaminergic activity
SSRIs are well suited for patients presenting with significant mood disorders, particularly those not tolerant to TCA side effects
Combination of SSRIs with low-dose TCAs can be synergic
Monoamine oxidase inhibitorsMonoamine oxidase inhibitors
MAOIs block monoamine breakdown after release from the neuron
MAOIs show greater efficacy than TCAs in treating atypical depression, a subtype of depression associated with chronic pain conditions
Anti-epileptic drugsAnti-epileptic drugs
AEDs increase the seizure threshold through sodium and calcium channel blockade or increasing inhibitory neurotransmission
Clonazepam may be a useful agent in FMS with TMD and leg restless syndrome
Neurontin is specific for post-herpetic neuralgia, and can treat a variety of pain
Sedative- hypnoticsSedative- hypnotics
Zopiclone and zolpodem at standard doses have been shown to improve sleep in FMS
The importance of improving sleep in FMS should not be under-rated, as a poor night’s sleep has been shown to result in more pain and fatigue the next day
Muscle relaxantsMuscle relaxants
Cyclobenzaprine is taken before sleep appears to improve sleep and pain in FMS
Morning hangover and dry mouth is its common side effects
Tizanidine is a centrally acting alpha-2 agonist for treatment of muscle spasticity associated with multiple sclerosis and stroke
A reduction in Sub P level in CSF of patients with FMS
OpiatesOpiates
The main problems are the effects on cognition, reduced motivation to pursue non-pharmacological treatment modalities, and aggravation of depression
Tramadol from 50mg bid to 100mg qid
Ultracet (tramadol 37.5mg + acetaminophen 325mg) is better tolerated than tramadol alone
QuestionsQuestions
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