Documente Academic
Documente Profesional
Documente Cultură
2017
Compendium of
Therapeutic Choices
Canada’s Trusted Reference for
Primary Care Therapeutics
Chapter 1: Fibromyalgia 1
Fibromyalgia
Chapter 1
Fibromyalgia
Chapter 1
Fibromyalgia is characterized by chronic widespread pain, increased tenderness at specific sites known
as “tender points,” unrefreshing sleep, fatigue and cognitive dysfunction not attributable to other
disease states. Fibromyalgia affects 2–4% of the general population and of those affected, 80–90% are
female. In general, symptom onset occurs between the ages of 30 and 60. Central and peripheral
system changes in terms of hypothalamic-pituitary-adrenal axis dysfunction, central sensitization,
wind-up (a progressive increase in sensitivity over time, i.e., lower stimuli result in increased pain),
elevated excitatory neurotransmitters, vasoconstriction, ischemia and adrenergic receptor sensitivity
have been described, although none have been identified as clear causative factors.
While the etiology of fibromyalgia is not entirely clear, associations with trauma, adverse life events,
impaired mood (e.g., depression), anxiety, irritable bowel syndrome, irritable bladder syndrome, cold
intolerance, paresthesias and other medical conditions have been described.1 Consequently, a patient-
tailored approach to treatment is ideal to address both symptoms of fibromyalgia and any associated
conditions.
Goals of Therapy
■ Reduce pain, fatigue, psychological distress and sleep problems
■ Improve physical and emotional well-being, functioning and quality of life
■ Address associated conditions on an individual basis
■ Promote self-management via individual and group education
Investigations
■ The American College of Rheumatology (ACR) has published provisional diagnostic criteria that
provide a case definition for fibromyalgia based on the widespread pain index (WPI) and the
symptom severity scale (SSS) (see Figure 1).2,3
■ The ACR tender point examination is also a tool that may be used for the diagnosis of fibromyalgia
(see Figure 2).
■ A physical examination, basic laboratory bloodwork and an inquiry as to the distribution and
duration of pain and any weakness should be undertaken (see Figure 3).
The Canadian Rheumatology Association and Canadian Pain Society recently endorsed similar
diagnostic criteria to the updated ACR criteria indicating that “examination for tender points is not
required to confirm the diagnosis.”4 A 2015 study found that the 1990 ACR criteria (using tender-point
examination) and the new 2010 ACR criteria are equally effective in diagnosing patients with
fibromyalgia as well in assessing the severity and outcome of the disease.5 The new criteria have not
yet been widely adopted by physicians. They are a simple tool for use in primary care for a condition
that all clinicians agree is complex. The diagnosis of fibromyalgia will continue to evolve with greater
understanding of the pathogenesis of the condition.
a Consider: muscle pain, irritable bowel syndrome, fatigue/tiredness, thinking or remembering problem, muscle weakness, headache, pain/cramps in the
abdomen, numbness/tingling, dizziness, insomnia, depression, constipation, pain in the upper abdomen, nausea, nervousness, chest pain, blurred vision,
fever, diarrhea, dry mouth, itching, wheezing, Raynauds phenomenon, hives/welts, ringing in ears, vomiting, heartburn, oral ulcers, loss of or change in
taste, seizures, dry eyes, shortness of breath, loss of appetite, rash, sun sensitivity, hearing difficulties, easy bruising, hair loss, frequent urination, painful
urination, bladder spasms.
Adapted with permission from Wolfe F, Clauw D, Fitzcharles MA et al. 2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria Semin Arthitis Rheum
2016;46(3):319-329.
Therapeutic Choices
Nonpharmacologic Choices
Nonpharmacologic treatment of fibromyalgia should be first-line therapy, especially due to a lack of
strong data to support the use of medications.
■ Empathy and acknowledgment of suffering from healthcare providers is fundamental.
■ A comprehensive, multidisciplinary program of education, self-management, nonpharmacologic
pain reduction techniques, graded aerobic exercises, sleep hygiene, stress management and
cognitive behavioural therapy is believed to be beneficial,6 but a Cochrane review indicated too few
high-quality randomized controlled trials to support this common viewpoint.7 A “person-centred”
approach to care has been advocated.8
Pharmacologic Choices
Drug therapies for the management of fibromyalgia are presented in Table 1.
Because the etiology of fibromyalgia remains unknown, drug treatments are largely empiric. Patients
should receive individualized pharmacotherapy tailored to treat their symptoms. Studies have been of
Antidepressants
A wide range of antidepressants have been used in the management of fibromyalgia, including tricyclic
antidepressants, selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake
inhibitors (SNRIs).20,21
Low doses of amitriptyline at bedtime (e.g., starting at 5 mg and progressing slowly, every 2–3
weeks, to a maximum of 50 mg) can improve sleep and reduce pain and fatigue.22 Only short-term
efficacy has been shown (≤8 weeks).22 A Cochrane review suggests that although it is an appropriate
initial treatment, only a minority of patients will achieve satisfactory pain relief with amitriptyline.23 If
taken 1–2 hours before bedtime, the effect will start at bedtime, and morning hangover will be
lessened.
The SNRI duloxetine does not improve fatigue, quality of life or sleep disturbances but provides a
small reduction in fibromyalgia pain.24 Duloxetine is generally well tolerated but some patients may
discontinue its use due to nausea, dry mouth, constipation or headache. Duloxetine may be considered
as first-line drug therapy in fibromyalgia patients with concomitant depression. Venlafaxine has not
been studied in patients with fibromyalgia. However, milnacipran, an SNRI not available in Canada,
was shown to be beneficial in treating fibromyalgia symptoms.25 Levomilnacipran is marketed in
Canada but is indicated only for short-term management of major depressive disorder and has not been
studied for the management of fibromyalgia.
Although SSRIs have been commonly used in the management of fibromyalgia, a 2015 systematic
review and meta-analysis suggests that they have a minimal effect on pain and global improvement,
and no effect on sleep or fatigue.26 SSRIs can be considered in patients with fibromyalgia and
concomitant depression.26,22 Fluoxetine in the morning with evening amitriptyline was more
effective than either agent alone in a double-blind controlled trial in fibromyalgia sufferers.27
GABA Derivatives
In clinical trials, substantial pain reduction (≥50% pain intensity reduction) with pregabalin was
demonstrated in about 10% more patients than placebo.28 Similarly, a moderate pain reduction (≥30%
pain intensity reduction) was observed in about 11% more patients than placebo. Pain relief with
pregabalin was also accompanied by improvement in quality of life, sleep and function.29 Pregabalin
was shown to be beneficial at doses of 300–450 mg/day; doses higher than 450 mg did not produce
greater symptom improvement, while lower doses (150 mg/day) were not different from placebo.
Doses of pregabalin should be titrated slowly upward, beginning with 25–50 mg at bedtime, to
minimize adverse effects (drowsiness, dizziness). There is also evidence that gabapentin may improve
pain scores and sleep in patients with fibromyalgia,30 although it has not been as extensively studied as
pregabalin in this patient population.
Other Drugs
Analgesics such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) may be tried
but help very few patients. These drugs may not be useful for fibromyalgia because the pain is
probably a result of central sensitization rather than peripheral pain or inflammation.
Cyclobenzaprine, a “muscle relaxant” that is structurally similar to tricyclic antidepressants, is
somewhat effective in fibromyalgia, particularly in improving sleep.31
Tramadol (with or without acetaminophen) has been reported to reduce pain and to improve health-
related quality of life in individuals with fibromyalgia.32,33,34,35 This effect, however, is likely due to
Therapeutic Tips
■ The treatment of arthritis, hypothyroidism, peripheral neuropathy and other medical conditions may
be complicated by concomitant fibromyalgia.
■ Although there is no clear causal relationship, patients with fibromyalgia are more likely to meet
the criteria for post-traumatic stress disorder.57 Similarly, patients with fibromyalgia are more likely
to suffer from certain conditions, e.g., depression, irritable bowel syndrome, chronic low-back
pain.58
■ If drug therapy is appropriate, pharmacologic agents work best when combined with
nonpharmacologic modalities, ideally as part of a multidisciplinary treatment program.6
■ Patients may also require a combination of drugs with different mechanisms of action.
■ It is important to document not only reduced pain but also improved function.
■ In the experience of the author and other clinicians, patients with fibromyalgia may be unduly
sensitive to drug side effects; a rational approach is to start medications at low doses and increase
slowly by small increments.
a AST, alkaline phosphatase, calcium, CBC, creatine kinase, creatinine, CRP, ESR, TSH and 25-hydroxyvitamin D.
b Associated disorders include mood disturbances, cognitive dysfunction, irritable bowel syndrome, irritable bladder syndrome, dizziness, cold intolerance,
subjective swelling, paresthesia, migraine, severe menstrual pain, myofascial facial pain, sexual dysfunction and temporomandibular joint syndrome.
c CBC, creatine kinase, ESR, CRP and TSH.
Abbreviations: AST = aspartate aminotransferase; CBC = complete blood count; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; TSH =
thyroid-stimulating hormone
8
Table 1: Drugs Used the Management of Fibromyalgia
Class Drug Dosage Adverse Effects Drug Interactions Costa
Analgesics acetaminophenb 325–1000 mg Q4H po Hepatotoxicity with chronic Excessive alcohol intake may $
Tylenol, Atasol Preparations, Maximum dose: 4 g/day high doses or in acute increase the risk of hepatotoxicity.
Fibromyalgia
generics overdose. Acetaminophen has been reported to
increase INR in warfarin-treated
patients.59 Check INR if
acetaminophen ≥2 g/day is used for
≥3 consecutive days. Adjust warfarin
dosage as required.
tramadol extended-release b Durela, Ralivia or Tridural: Somnolence, dizziness, Possible increased risk of seizure with $$$$$
Durela, Ralivia, Tridural, Zytram Start with 100 mg once daily flushing, constipation, SSRIs, MAO inhibitors, tricyclic
XL, generics po; may increase at weekly nausea, pruritus, seizures, antidepressants and other tricyclic
intervals to maximum anaphylactoid reactions, compounds, antipsychotics,
300 mg daily dependence, withdrawal amphetamines, linezolid, opioids or
Zytram XL: Start with 150 mg syndrome. drugs that reduce the seizure
once daily po; may increase Risk of respiratory threshold.
at weekly intervals to depression in ultra-rapid Use with SSRIs or MAO inhibitors may
maximum 400 mg daily metabolizers of CYP2D6. also increase risk of serotonin
Depending on ethnicity, syndrome.
1–28% of the population Use with CNS depressants may
ultra-rapidly metabolize increase the risk of CNS and
tramadol to the more potent respiratory depression.
opioid metabolite
Carbamazepine may increase the
o-desmethyltramadol.60
metabolism of tramadol. Also,
tramadol may increase the risk of
seizures in patients taking
anticonvulsants.
tramadol with acetaminophen b Use lowest dose possible to See tramadol extended- See acetaminophen. $$$$$
Tramacet, Tramadol/ achieve pain control release. See tramadol extended-release.
Acetamoniphen, other generics 1–2 tablets Q4–6H po PRN
Maximum dose: 8 tablets
(300 mg tramadol + 2600 mg
acetaminophen) daily
GABA Derivatives Starting dose: 100 mg QHS Sedation, ataxia, tremor; Administration with aluminum/
Compendium of Therapeutic Choices
gabapentin b $$
Neurontin, Gabapentin po; titrate slowly as tolerated less commonly, GI upset, magnesium-containing antacids may
Capsules, Gabapentin Tablets, to 1200–2400 mg/day (in 2– peripheral edema, vision decrease bioavailability. May have
other generics 3 divided doses) changes, weight gain. enhanced CNS depressant effects
when coadministered with other CNS
depressants.
(cont'd)
Compendium of Therapeutic Choices
pregabalin b Starting dose: 25–50 mg Sedation, dizziness, May have enhanced CNS depressant $$
Lyrica, Pregabalin, Pregabalin QHS po; titrate slowly as cognitive impairment, dry effects when coadministered with
25/50/75/150, tolerated to 300–450 mg/day mouth, peripheral edema. other CNS depressants. May cause
other generics (in 2 divided doses) peripheral edema/weight gain when
coadministered with
thiazolidinediones (pioglitazone,
rosiglitazone).
Nonsteroidal Anti- ibuprofenb 200–600 mg Q6H po Peptic ulcer, dyspepsia, Warfarin: increased anticoagulant $
inflammatory Advil, Motrin, Motrin IB Super Maximum dose: 2400 mg/ hypersensitivity, fluid effect.
Drugsc Strength Liquid Gels Capsules, day retention, hypertension, Antihypertensives: possible decrease
Motrin Liquid Gels 200 mg, renal toxicity. in hypertensive effect.
Motrin Liquid Gels 400 mg, Increased risk of serious CV Lithium: may interfere with sodium/
generics events (e.g., MI or stroke) water balance. Monitor lithium levels
with doses ≥2400 mg/day. when NSAID added.
Increased risk of GI bleeding when
used with SSRIs.
Serotonin- duloxetine 30–60 mg once daily po Nausea, headache, Alcohol, CNS depressants. $$
Norepinephrine Cymbalta, generics Maximum dose: 120 mg/day drowsiness, insomnia, MAO inhibitors may cause serotonin
Reuptake (divided BID) dizziness, dry mouth. syndrome (severe reaction—tremor,
Inhibitors Do not use in patients with agitation, hypomania, hypertension).
severe renal impairment Tramadol may also increase risk of
(ClCr <30 mL/min). serotonin syndrome.
Do not use with potent CYP1A2
inhibitors (e.g., ciprofloxacin,
fluvoxamine, ketoconazole). CYP2D6
inhibitors (e.g., SSRIs) may increase
duloxetine levels.
Chapter 1: Fibromyalgia
(cont'd)
Copyright © . All rights reserved.
9
Table 1: Drugs Used the Management of Fibromyalgia (cont'd)
Copyright © . All rights reserved.
10
Class Drug Dosage Adverse Effects Drug Interactions Costa
Selective fluoxetineb 10–20 mg QAM po (better Nausea, dry mouth, MAO inhibitors may cause severe $
Serotonin Prozac, Fluoxetine, other efficacy in 1 trial when somnolence, sweating, reaction—tremor, agitation,
Reuptake generics combined with amitriptyline sexual dysfunction. hypomania, hypertension. Drugs that
Fibromyalgia
Inhibitors in the evening)27 Increased risk of GI inhibit CYP enzymes (e.g., cimetidine,
Maximum dose: 60 mg/day bleeding. clarithromycin, erythromycin,
fluconazole, indinavir, isoniazid,
itraconazole, ketoconazole, quinidine,
ritonavir) may increase SSRI levels.
All SSRIs inhibit certain CYP
isoenzymes and can decrease the
clearance of other drugs (e.g.,
clozapine, methadone, mexiletine,
phenytoin, pimozide, propafenone).
Inducers of CYP enzymes (e.g.,
carbamazepine, phenobarbital,
phenytoin, rifampin) can increase the
clearance of SSRIs.
Increased risk of GI bleeding with
NSAIDs.
Tricyclic Agentsc amitriptylineb 5–50 mg po 1–2 h before Anticholinergic (dry mouth, Combination with MAO inhibitors may $
Elavil, generics bedtime (start low and titrate blurred vision, constipation, result in mania, excitation,
slowly) urinary hesitancy, hyperpyrexia; barbiturates,
tachycardia, delirium), carbamazepine and rifampin may
antihistaminergic (sedation, decrease effect; cimetidine and
weight gain), orthostatic antipsychotics may increase effect
hypotension, lowered and toxicity; possible interaction with
seizure threshold; sexual antiarrhythmics (may lead to
dysfunction. increased effect of either drug); may
decrease antihypertensive effect of
clonidine; may increase hypotensive
effect of thiazides.
effective61
a Cost of 30-day supply of mean dose; includes drug cost only.
b Not a Health Canada-approved indication.
c Listed drugs are examples of medications in this class.
Dosage adjustment may be required in renal impairment; see Appendix I.
Abbreviations: CYP = cytochrome P450; MAO = monoamine oxidase; SSRI = selective serotonin reuptake inhibitor
Legend: $ <$15 $$ $15–30 $$$ $30–45 $$$$ $45–60 $$$$$ $60–75
Chapter 1: Fibromyalgia 11
Suggested Readings
Clauw DJ. Fibromyalgia: an overview. Am J Med 2009;122(12 Suppl):S3-13.
Fitzcharles MA, Ste-Marie PA, Pereira JX et al. Fibromyalgia: evolving concepts over the past 2
decades. CMAJ 2013;185(13):E645-51.
Kodner C. Common questions about the diagnosis and management of fibromyalgia. Am Fam
Physician 2015;91(7):472-8.
Macfarlane GJ, Kronisch C, Dean LE et al. EULAR revised recommendations for the management of
fibromyalgia. Ann Rheum Dis 2017;76(2):318-28.
Wolfe F, Clauw DJ, Fitzcharles M et al. 2016 revisions to the 2010/2011 fibromyalgia diagnostic
criteria. Semin Arthitis Rheum2016;46(3):319-329.
References
1. Abeles AM, Pillinger MH, Solitar BM et al. Narrative review: the pathophysiology of fibromyalgia. Ann Intern Med 2007;146(10):726-34.
2. Wolfe F, Clauw DJ, Fitzcharles MA et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and
measurement of symptom severity. Arthritis Care Res (Hoboken) 2010;62(5):600-10.
3. Wolfe F, Clauw DJ, Fitzcharles M et al. 2016 revisions to the 2010/2011 fibromyalgia diagnostic criteria. Semin Arthitis Rheum2016;46
(3):319-329.
4. Fitzcharles MA, Ste-Marie PA, Pereira JX et al. Fibromyalgia: evolving concepts over the past 2 decades. CMAJ 2013;185(13):E645-51.
5. Moyano S, Kilstein JG, Alegre de Miguel C. New diagnostic criteria for fibromyalgia: here to stay? Reumatol Clin 2015;11(4):210-4.
6. Bennett RM. Multidisciplinary group programs to treat fibromyalgia patients. Rheum Dis Clin North Am 1996;22(2):351-67.
7. Karjalainen K, Malmivaara A, van Tulder M et al. Multidisciplinary rehabilitation for fibromyalgia and musculoskeletal pain in working age
adults. Cochrane Database Syst Rev 2000;(2):CD001984.
8. Masi AT, White KP, Pilcher JJ. Person-centered approach to care, teaching, and research in fibromyalgia syndrome: justification from
biopsychosocial perspective in populations. Semin Arthritis Rheum 2002;32(2):71-93.
9. Bennett R, Nelson D. Cognitive behavioral therapy for fibromyalgia. Nat Clin Pract Rheumatol 2006;2(8):416-24.
10. Busch AJ, Barber KA, Overend TJ et al. Exercise for treating fibromyalgia syndrome. Cochrane Database Syst Rev 2007;(4):CD003786.
11. Wang C, Schmid CH, Rones R et al. A randomized trial of tai chi for fibromyalgia. N Engl J Med 2010;363(8):743-54.
12. Busch AJ, Webber SC, Richards RS et al. Resistance exercise training for fibromyalgia. Cochrane Database Syst Rev 2013;(12):CD010884
13. Bidonde J, Busch AJ, Webber SC et al. Aquatic exercise training for fibromyalgia. Cochrane Database Syst Rev 2014;(10):CD011336.
14. Brosseau L, Wells GA, Tugwell P et al. Ottawa Panel evidence-based clinical practice guidelines for aerobic fitness exercises in the
management of fibromyalgia: part 1. Phys Ther 2008;88(7):857-71.
15. Hassett AL, Gevirtz RN. Nonpharmacologic treatment for fibromyalgia: patient education, cognitive-behavioral therapy, relaxation
techniques, and complementary and alternative medicine. Rheum Dis Clin North Am 2009;35(2):393-407.
16. Deluze C, Bosia L, Zirbs A et al. Electroacupuncture in fibromyalgia: results of a controlled trial. BMJ 1992;305(6864):1249-52.
17. Langhorst J, Klose P, Musial F et al. Efficacy of acupuncture in fibromyalgia syndrome—a systematic review with a meta-analysis of
controlled clinical trials. Rheumatology (Oxford) 2010;49(4):778-88.
18. Deare JC, Zheng Z, Xue CC et al. Acupuncture for treating fibromyalgia. Cochrane Database Syst Rev 2013;5:CD007070.
19. Finestone HM, Stenn P, Davies F et al. Chronic pain and health care utilization in women with a history of childhood sexual abuse. Child
Abuse Negl 2000;24(4):547-56.
20. Uceyler N, Hauser W, Sommer C. A systematic review on the effectiveness of treatment with antidepressants in fibromyalgia syndrome.
Arthritis Rheum 2008;59(9):1279-98.
21. Hauser W, Bernardy K, Uceyler N et al. Treatment of fibromyalgia syndrome with antidepressants: a meta-analysis. JAMA 2009;301(2):198-
209.
22. Macfarlane GJ, Kronisch C, Dean LE et al. EULAR revised recommendations for the management of fibromyalgia. Ann Rheum Dis 2017;76
(2):318-28.
23. Moore RA, Derry S, Aldington D et al. Amitriptyline for fibromyalgia in adults. Cochrane Database Syst Rev 2015;7:CD011824.
24. Hauser W, Urrutia G, Tort S et al. Serotonin and neoradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome. Cochrane Database
Syst Rev 2013;1:CD010292.
25. Cording M, Derry S, Phillips T et al. Milnacipran for pain in fibromyalgia in adults. Cochrane Database Syst Rev 2015;(10):CD008244.
26. Walitt B, Urrútia G, Nishishinya MB et al. Selective serotonin reuptake inhibitors for fibromyalgia syndrome. Cochrane Database Syst Rev
2015;(6):CD011735.
27. Goldenberg D, Mayskiy M, Mossey C et al. A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of
fibromyalgia. Arthritis Rheum 1996;39(11):1852-9.
28. Derry S, Cording M, Wiffen PJ et al. Pregabalin for pain in fibromyalgia in adults. Cochrane Database Syst Rev 2016;9:CD011790.
29. Hauser W, Bernardy K, Uceyler N et al. Treatment of fibromyalgia syndrome with gabapentin and pregabalin—a meta-analysis of randomized
controlled trials. Pain 2009;145(1-2):69-81.
30. Moore RA, Wiffen PJ, Derry S et al. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2014;
(4):CD007938.
31. Tofferi JK, Jackson JL, O'Malley PG. Treatment of fibromyalgia with cyclobenzaprine: a meta-analysis. Arthritis Rheum 2004;51(1):9-13.
32. Biasi G, Manca S, Manganelli S et al. Tramadol in the fibromyalgia syndrome: a controlled clinical trial versus placebo. Int J Clin Pharmacol
Res 1998;18(1):13-9.
33. Russell IJ, Kamin N, Bennett RM et al. Efficacy of tramadol in treatment of pain in fibromyalgia. J Clin Rheumatol 2000;6(5):250-7.
34. Bennett RM, Kamin M, Karim R et al. Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: a double-blind,
randomized, placebo-controlled study. Am J Med 2003;114(7):537-45.