Lyrica for Fibromyalgia

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Lyrica for Fibromyalgia

Background

Fibromyalgia is a chronic syndrome characterized by generalized muscular pain and fatigue. Patients with this syndrome will often complain of achiness all over, inability to sleep well, stiffness on waking, tiredness during the day, depression, anxiety, or cognitive disturbances.1 It is estimated that approximately 2% of the U.S. population has fibromyalgia and it is more common in women than in men.2

Historically, the diagnosis of fibromyalgia has been controversial, with some people doubting the existence of the syndrome.2,3 With the development of diagnostic criteria by the American College of Rheumatology, practitioners are now able to distinguish fibromyalgia from other forms of chronic musculoskeletal pain. Criteria for classification of fibromyalgia include widespread pain (left and right side, above and below the waist, in the axial skeleton) for at least three months. Also, palpable pain in at least 11 of 18 identified tender point sites must also be present.4

As is the case with many types of chronic pain syndromes, effective management of fibromyalgia remains challenging. Both pharmacologic and nonpharmacologic treatments have been used in patients with fibromyalgia.

On June 21, 2007, Lyrica (pregabalin) became the first drug approved by the FDA for the management of fibromyalgia. In the U.S., Lyrica was already approved for the management of neuropathic pain associated with diabetic peripheral neuropathy and for postherpetic neuralgia in adults and as an adjunctive therapy for adults with partial onset seizures. This document reviews the efficacy and adverse effects of Lyrica and other commonly used drugs for the management of fibromyalgia.

Lyrica for Fibromyalgia

Lyrica (pregabalin) is a 3-substituted analogue of gamma-amino butyric acid (GABA) that binds selectively to the alpha-2-delta subunit of the voltage-gated calcium channel.5,6

The exact mechanism of action of Lyrica is unknown. It's proposed that the binding to the alpha-2-delta subunit of the calcium channel decreases calcium influx at nerve terminals and reduces the release of several neurotransmitters, including glutamate, norepinephrine, and substance P.5 The inhibition of neurotransmitter release results in analgesic, anticonvulsant, and anxiolytic effects.5 The recommended total daily dose of Lyrica for fibromyalgia is 300 mg to 450 mg per day. Dosing should start with 75 mg two times a day and increase to 150 mg two times a day within a week based on efficacy and tolerability. For those who do not experience sufficient relief with Lyrica 150 mg two times a day, dosage can be titrated to 225 mg two times a day. Doses above 450 mg per day have not been shown to be more effect and are associated with a higher incidence of adverse events.5

The FDA approved Lyrica for the management of fibromyalgia based on results of a 14-week double-blind, placebo-controlled, multicenter study and a six month randomized withdrawal study.7 Patients enrolled in the studies all have a diagnosis of fibromyalgia based on the American College of Rheumatology (ACR) criteria.

In the 14-week study, the efficacy of Lyrica in patients with fibromyalgia was compared to placebo. The primary endpoint was mean change in pain score. After one week of single-blind placebo run-in period, patients with a minimum mean baseline pain score of >4 on an 11-point numeric pain rating scale and a score of greater than or equal to 40 mm on the 100 mm pain visual analog scale (VAS) were enrolled in the double-blind treatment phase (n=745, mean age= 50). The baseline mean pain score in this trial was 6.7 and the median fibromyalgia duration was ten years. Patients who responded to placebo in an initial one-week run-in phase were not randomized to subsequent phases of the study.5,7

Results of this study showed that 47.6% of patients treated with placebo reported any improvement in fibromyalgia symptoms compared to 68.1% treated with Lyrica 300 mg per day, 77.8% treated with Lyrica 450 mg per day, and 66.1% treated with Lyrica 600 mg per day. At the end of 14 weeks, the mean change in pain score from baseline for Lyrica 300 mg/day was -0.71 (p=0.0009), for 450 mg/day was -0.98 (p<0.0001), for 600 mg/day was -1.00 (p<0.0001).7 Lyrica 450 mg and 600 mg/day groups had significant improvement in FIQ total score and medical outcomes study (MOS)-sleep scale (secondary objectives).7 There was an increase in adverse events with higher doses of Lyrica. The authors concluded that Lyrica was more effective in improving global assessment, functional status and sleep in patients with fibromyalgia compared to placebo. Total daily dose of Lyrica 600 mg showed no more benefit than lower doses and was associated with increased adverse events.5,7

In the six-month randomized withdrawal study (n=1051, 93% female; mean age=50 years old), the durability of Lyrica for pain associated with fibromyalgia was evaluated in patients who initially responded to open-label Lyrica treatment. The study consisted of a one-week baseline screening phase, then a six-week open-label treatment phase, a 26-week double-blind treatment phase, and a one-week follow-up period.5,7

During the open-label phase, patients were treated with Lyrica 75 mg twice daily, then increased to 150 mg twice daily by the first week. Further dosage titration was done over the next two weeks to 225 mg twice daily or 300 mg twice daily if needed. Patients with >50% reduction in mean pain VAS score from open label baseline and who scored 'much improved' or 'very much improved on the Patient Global Impression of Change (PGIC) at two of the final three visits were enrolled in the double-blind phase (n=556).

At the end of the 26 week period, results showed that the time to loss of therapeutic response was significantly longer for patients treated with Lyrica compared to placebo. A quarter of the patients experienced loss of therapeutic response by day seven in the placebo group and a quarter of the patients experienced loss of therapeutic response by day 34 in the Lyrica group (p<0.001). Fifty-three percent of the Lyrica-treated patients compared to 33% of placebo patients remained on the study treatment and maintained a therapeutic response at week 26 of the study.5,7 The efficacy of Lyrica beyond six months in the treatment of fibromyalgia is unknown.

In another eight week randomized, double-blind, parallel-group, placebo-controlled study (n=529, intent-to-treat population, 91.5% female, mean age=48.6), patients with fibromyalgia were treated with Lyrica 150 mg/day, 300 mg/day, 450 mg/day, or placebo in three divided doses for eight weeks. The primary endpoint was mean pain score reduction. The results showed that patients treated with Lyrica 450 mg/day were more likely to have a >50% reduction in pain compared to placebo (28.9% vs. 13.2%; p=0.003). Patients treated with Lyrica 150 mg and 300 mg/day did not reach significant difference in mean pain scores from placebo. Forty-eight percent of patients treated with Lyrica 450 mg/day had at least a 30% reduction in pain compared to 27.1% of patients treated with placebo (p=0.003).7

The most commonly reported adverse events in clinical trials were dizziness and somnolence. Other reported adverse events included, but were not limited to, edema, headaches, arthralgia, and anxiety.5

Other Pharmacologic Treatments

The exact cause of fibromyalgia is unknown, but an imbalance of serotonin and norepinephrine are thought to be involved. These neurotransmitters are involved in the transmission of pain signals.3,8,9 Agents that modulate these neurotransmitters (specifically those that block reuptake of serotonin and norepinephrine) are often used to treat patients with fibromyalgia.5 Among these agents, tricyclic antidepressants (especially amitriptyline [Elavil, etc]) and cyclobenzaprine (Flexeril, a muscle relaxant structurally related to the tricyclics) have the largest supporting evidence for use in patients with fibromyalgia.2,9 Tricyclic agents inhibit both serotonin and norepinephrine reuptake and have been shown to reduce pain, fatigue, and sleep dysfunction symptoms.9 These effects are independent of the antidepressant effects of TCAs.9 Amitriptyline and cyclobenzaprine have been shown to have a modest benefit in short-term trials.10,11 There is limited data on the efficacy of these agents long-term.10,11 These agents seem to be especially beneficial for improving quality of sleep.2,3 Amitriptyline doses in fibromyalgia trials have ranged from 5 mg to 50 mg/day at bedtime (dose generally titrated up to effect or as tolerated).3,12 Cyclobenzaprine has been studied utilizing escalating doses of 10 mg to 40 mg per day (divided doses).10

Nontricyclic antidepressants have also been tried in patients with fibromyalgia. Duloxetine (Cymbalta), a selective serotonin and norepinephrine reuptake inhibitor (SNRI) has been used in the management of fibromyalgia. In a 12-week, randomized, double-blind, placebo-controlled trial, the efficacy of duloxetine (60 mg twice a day) was assessed in 207 patients (184 women, 23 men) with fibromyalgia.8 Even though duloxetine did not significantly improve the Fibromyalgia Impact Questionnaire pain score (one of two primary outcomes) compared to placebo, it was associated with significant improvements in many other outcome measures in patients with or without depression. The male patients taking duloxetine (n=12) did not improve significantly on any efficacy measure. Short-term treatment of fibromyalgia with duloxetine looks promising, but long-term efficacy still needs to be assessed. Similar results were seen in another 12- week, placebo-controlled trial with two doses of duloxetine (60 mg daily or twice daily).12 Pain reduction with duloxetine was independent of effects on mood or anxiety. This suggests that duloxetine provides analgesia by a mechanism other than its mood-enhancing action.8,12 Although duloxetine was shown to be effective in the management of pain and depression symptoms of fibromyalgia, it did not appear have any beneficial effects on sleep dysfunction associated with fibromyalgia as seen with amitriptyline.9 Venlafaxine (Effexor), another serotonin and norepinephrine reuptake inhibitor, has shown some benefit in two small open-label studies, but in a randomized controlled trial of 90 patients it was not found to be significantly different from placebo.2,13,14

Trials of the selective serotonin reuptake inhibitor (SSRI) fluoxetine (Prozac, etc) for fibromyalgia have produced inconsistent results with some showing benefit and others not.2 However, the combination of fluoxetine and amitriptyline has been shown to be better than either drug alone.2 The low-dose tricyclic also helps to counteract the potential negative impact of the SSRI on sleep.3 Keep in mind, fluoxetine can inhibit the metabolism of tricyclic antidepressants leading to an increase in their levels.15

Some analgesic agents have been shown to be useful adjuncts for pain control in patients with fibromyalgia. Tramadol, with or without acetaminophen (Ultracet or Ultram, respectively), has shown some benefit in randomized controlled trials.2,16 Nonsteroidal anti-inflammatory agents (NSAIDs) when used alone do not appear very effective.2,3 While traditional opioids are used for many chronic pain syndromes, there haven't been any controlled trials in patients with fibromyalgia.2 Their use is considered by some experts, but only when all other options have failed.2

Another drug demonstrating some beneficial effects in the management of fibromyalgia is gabapentin (Neurontin). Neurontin is structurally similar to Lyrica. In a 12-week randomized, double-blind study, placebo-controlled study (n=75), patients treated with gabapentin 1,200 to 2,400 mg/day showed a significantly greater improvement in the Brief Pain Inventory (BPI) average pain severity score compared to placebo.17 A significantly greater proportion of gabapentin-treated patients compared with placebo-treated patients achieved response at the end of 12 weeks (51% versus 31%; P=0.014). Gabapentin compared with placebo also significantly improved the BPI average pain interference score, the Fibromyalgia Impact Questionnaire total score, the Clinical Global Impression of Severity, the Patient Global Impression of Improvement, the Medical Outcomes Study (MOS) Sleep Problems Index, and the MOS Short Form 36 vitality score, but not the mean tender point pain threshold or the Montgomery Asberg Depression Rating Scale. Gabapentin was generally well tolerated.17

Some drugs being investigated for the treatment of fibromyalgia include sodium oxybate (Xyrem), pramipexole (Mirapex), ropinirole (Requip), modafinil (Provigil), milnacipran (not available in the U.S. or Canada), levetiracetam (Keppra), zonisamide (Zonegran), hydrocortisone, growth hormone, etc.9 Sodium oxybate, the prescription form of GHB (gamma-hydroxybutyrate), is available through a restricted distribution program to treat cataplexy in patients with narcolepsy. In very preliminary studies, sodium oxybate has shown some benefits in reducing fibromyalgia-associated pain, fatigue, and alpha sleep anomaly.9,18 Agents for which there is not enough evidence to support their use in fibromyalgia include milnacipran, pramipexole, ropinirole, benzodiazepines, corticosteroids, calcitonin, thyroid hormone, and guaifenesin (no significant benefit seen in one controlled trial).2,9,19

Nonbenzodiazepines such as zolpidem (Ambien) and zopiclone (Imovane, available in Canada) have limited evidence to show that they are beneficial in managing sleep disturbances associated with fibromyalgia, but these agents only affect the onset of sleep and not sleep maintenance.9 Eszopiclone (Lunesta) is effective in improving sleep onset, duration, and maintenance in nonelderly adults with chronic insomnia, but there are no data on it use in fibromyalgia patients.9

Nonpharmacologic Treatments

Some nonpharmacologic interventions (e.g., exercise, cognitive behavioral therapy, biofeedback, hypnosis, acupuncture, etc) have stronger evidence of benefit than others. Aerobic exercise and muscle strengthening have been shown to be beneficial in patients with fibromyalgia (stronger supporting evidence for aerobic exercise).2,16,20 Cognitive behavioral therapy has been shown to improve pain, fatigue, mood, and function.2 Various combinations of the above interventions have also demonstrated positive outcomes. There is moderate evidence for efficacy with biofeedback, hypnosis, and acupuncture.

Supplements and Fibromyalgia

Some patients may inquire about supplements to treat their fibromyalgia. S-adenosylmethionine (SAMe) is a supplement with anti-inflammatory, analgesic, and antidepressant effects. There is some evidence from small studies that SAMe might be beneficial for patients with fibromyalgia (intravenous administration has failed to show a benefit). For fibromyalgia, an oral dose of
800 mg per day is typically used.21

Another supplement with some evidence of effectiveness is 5-hydroxytryptophan (5-HTP), a metabolite of L-tryptophan that is eventually converted to serotonin.22 It must be noted there is controversy concerning the safety of 5-HTP, which has been linked to cases of eosinophilia myalgia syndrome (EMS). It's not certain if EMS is caused by 5-HTP, product contaminants, or other factors. Patients should avoid use of 5-HTP until there is more information concerning its safety.22

There is some very preliminary evidence that a product containing malic acid (200 mg) and magnesium (50 mg) per tablet (Super Malic) might help relieve pain and tenderness of fibromyalgia in doses of four to six tablets twice daily.23 Also, application of capsaicin cream to tender points may provide some relief.24 There is no evidence from controlled trials to support the use of dehydroepiandrosterone or melatonin.2

Conclusion

Fibromyalgia has traditionally been a difficult syndrome to manage because the symptoms and their severity can differ from patient to patient. What works for one patient may not work for another. At this time, Lyrica is the only agent that is FDA approved for the treatment of fibromyalgia. However, results of clinical trials showed only modest efficacy in pain relief compared to placebo. In addition, this efficacy can wane after weeks or months [Evidence level A; high quality RCT].5,7 Aside from Lyrica, agents such as amitriptyline and cyclobenzaprine have the most supporting evidence for use in patients with fibromyalgia [Evidence level B; nonquantitative systematic review].2 Nonmedicinal therapy such as exercise, cognitive behavioral therapy, and patient education also have strong evidence for efficacy as well.2

Once a diagnosis is made, patients and their families should be educated about fibromyalgia.2 Comorbid illnesses should be evaluated at this time. Patients should also be started on a low-impact aerobic exercise program and improve sleep hygiene.2,9,25 An initial trial with a low-dose tricyclic antidepressant or cyclobenzaprine should be considered.2,26 Cognitive behavioral therapy should also be considered at this time. If further intervention is needed, a trial of other medications (tramadol, an SSRI, or an SNRI), a combination of medications (e.g., SSRI and low-dose tricyclic), or use of anticonvulsants such as Lyrica or Neurontin might be beneficial.2,5,7 Note that the 2005 fibromyalgia guidelines did not mention anticonvulsants as an treatment option.26 However, based upon recent clinical data, the use of Lyrica in the treatment of fibromyalgia is acceptable and can be considered when other agents fail.5,7 If all of the above agents fail to relieve pain, some experts recommend using opioids even though there is limited evidence of their efficacy.2,26,27 Some experts also recommend nonbenzodiazepines (e.g., Ambien, etc) if sleep disturbances are a problem.9,26 Some experts also suggest benzodiazepines for the management of sleep disturbances if other agents fail to improve sleep.26 However, there is no evidence that these agents are safe and effective for the long-term treatment of sleep disturbances associated with fibromyalgia.9 Patients who don't respond to the above measures should be referred to a specialist (e.g., rheumatologist, pain management, etc).

Educating patients about fibromyalgia is important for optimal management of the syndrome.6 Sources of information about fibromyalgia include:

References

  1. American College of Rheumatology. Patient education for fibromyalgia. http://www.rheumatology.org/public/factsheets/fibromya_new.asp#1. (Accessed July 11, 2007)).
  2. Goldenberg DL, Burckhardt C, Crofford L. Management of fibromyalgia syndrome. JAMA 2004;292:2388-95.
  3. Fibromyalgia. Pharmacist's Letter/Prescriber's Letter 2000;16(12):161201.
  4. Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. http://www.rheumatology.org/publications/classification/fibromyalgia/fibro.asp. (Accessed July 11, 2007).
  5. Product information for Lyrica. Pfizer Inc, New York, NY 10017. June 2007.
  6. Lyrica (pregabalin) update. Pharmacist's Letter/Prescriber's Letter 2007;23(5):230513.
  7. Personal communication, medical information department. Pfizer Inc., New York, NY 10017. June 26, 2007.
  8. Arnold LM, Lu Y, Crofford LJ, et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum 2004;50:2974-84.
  9. Lawson K. Emerging pharmacological therapies for fibromyalgia. Curr Opin Investig Drugs 2006;7:631-6.
  10. Tofferi JK, Jackson JL, O'Malley PG. Treatment of fibromyalgia with cyclobenzaprine: a meta-analysis. Arthritis Rheum 2004;51:9-13.
  11. Arnold LM, Keck P, Welge JA. Antidepressant treatment of fibromyalgia. A meta-analysis and review. Psychosomatics 2000;41:104-13.
  12. Arnold LM, Rosen A, Pritchett YL, et al. A randomized double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain 2005;119:5-15.
  13. Sayar K, Aksu G, Ak I, Tosun M. Venlafaxine treatment of fibromyalgia. Ann Pharmacother 2003;37:1561-5.
  14. Grothe DR, Scheckner B, Albano D. Treatment of pain syndromes with venlafaxine. Pharmacotherapy 2004;24:621-9.
  15. Product information for Prozac. Eli Lilly and Co. Indianapolis, IN 46285. May 2007.
  16. Rooks DS, Fibromyalgia treatment update. Curr Opin Rheumatol 2007;19:111-17.
  17. Arnold LM, Goldenberg DL, Stanford SB, et al. Gabapentin in the treatment of fibromyalgia a randomized, double-blind, placebo-controlled multicenter trial. Arthritis Rheum 2007;56:1336-44.
  18. Jellin JM, Gregory PJ, et al. Gamma-hydroxybutyrate monograph. Pharmacist's Letter/Prescriber's Letter Natural Medicines Comprehensive Database. http://www.naturaldatabase.com. (Accessed July 11, 2007).
  19. Anon. Development of milnacipran for fibromyalgia hits a snag. Medscape medical news. October 4, 2005. http://www.medscape.com/viewarticle/538358. (Accesssed July 11, 2007).
  20. Busch A, Schachter CL, Pelosos PM, Bombardier C. Exercise for treating fibromyalgia syndrome. (Cochrane Review). In: The Cochrane Library, Issue 4, 2004. Chichester, UK: John Wiley & Sons, Ltd. (Abstract).
  21. Jellin JM, Gregory PJ, et al. SAMe monograph. Pharmacist's Letter/Prescriber's Letter Natural Medicines Comprehensive Database. http://www.naturaldatabase.com. (Accessed July 11, 2007).
  22. Jellin JM, Gregory PJ, et al. 5-HTP monograph. Pharmacist's Letter/Prescriber's Letter Natural Medicines Comprehensive Database. http://www.naturaldatabase.com. (July 11, 2007).
  23. Jellin JM, Gregory PJ, et al. Alpha hydroxy acids monograph. Pharmacist's Letter/Prescriber's Letter Natural Medicines Comprehensive Database. http://www.naturaldatabase.com. (Accessed July 11, 2007).
  24. Jellin JM, Gregory PJ, et al. Capsicum monograph. Pharmacist's Letter/Prescriber's Letter Natural Medicines Comprehensive Database. http://www.naturaldatabase.com. (Accessed July 11, 2007).
  25. University of Texas School of Nursing, Family Nurse Practitioner Program. Fibromyalgia treatment guideline. University of Texas, School of Nursing. 2005. http://guidelines.gov/summary/summary.aspx?doc_id=7352&nbr=004350&string=fibromyalgia. (Accessed July 18, 2007)
  26. Buckhardt CS, Goldenberg D, Crofford L, et al. Guideline for management of fibromyalgia syndrome pain in adults and children. American Pain Society, 2005. http://guidelines.gov/summary/summary.aspx?doc_id=7298&nbr=004342&string=fibromyalgia. (Accessed July 18, 2007).
  27. Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E. Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects. CMAJ 2006;174:1589-94.

Levels of Evidence

In accordance with the trend towards Evidence-Based Medicine, we are citing the LEVEL OF EVIDENCE for the statements we publish.

Level

Definition

A

High-quality randomized controlled trial (RCT)

High-quality meta-analysis (quantitative systematic review)

B

Nonrandomized clinical trial

Nonquantitative systematic review

Lower quality RCT

Clinical cohort study

Case-control study

Historical control

Epidemiologic study

C

Consensus

Expert opinion

D

Anecdotal evidence

In vitro or animal study

Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65:251-8.

Project Leader in preparation of this Detail-Document: Kim Palacioz, Pharm.D., Associate Editor (original), Wan-Chih Tom, Pharm.D. (August 2007 update)

Cite this Detail-Document as follows: Lyrica for fibromyalgia. Pharmacist's Letter/Prescriber's Letter 2007;23(8):230805.

August 2007

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