dr liu fibromyalgia disease overview-1

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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

3

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

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ain

in

ten

sity

Su

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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

1717

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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