Pregabalin (Lyrica) for fibromyalgia September 2007 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes. The Research Programme is part of the National Institute for Health Research
Target group Adults with fibromyalgia. Pregabalin (Lyrica) for fibromyalgia Background Fibromyalgia is a chronic condition characterised by muscle-tendon tenderness, pain in fibromuscular tissue, abdominal pain, fatigue, poor quality sleep, stiffness on waking, depression, temporo-mandibular joint dysfunction, headaches and multiple chemical sensitivity syndrome. The American Rheumatology Society (ARS) 1990 classification criteria state that for the diagnosis of fibromyalgia, the patient must have a history of widespread pain (chronic pain in all four quadrants of the body for at least 3 months) and experience excessive tenderness on at least 11 of 18 identified tender point sites 1. The pain associated with fibromyalgia is generally continuous, but can fluctuate in severity 2. There are currently no diagnostic tests to positively diagnose fibromyalgia. Technology description Pregabalin is an [alpha] 2 -[delta] ligand that has analgesic, anxiolytic and anticonvulsant properties. It is thought that pregabalin binds to voltage-gated calcium channels in the central nervous system, modifying the release of neurotransmitters. It is anticipated that pregabalin will be administered orally at doses of 150-600 mg per day divided into 2 or 3 doses. Pregabalin is currently licensed for: Epilepsy; Neuropathic pain; and Generalised anxiety disorder. Pregabalin is also in phase III clinical trials for HIV-associated neuropathy. Innovation and/or advantages There are currently no licensed drugs for fibromyalgia, therefore if licensed pregabalin may be one of the first specific drug treatments. Developer Pfizer Ltd. Place of use Home care e.g. home dialysis Secondary care e.g. general, non-specialist hospital General public e.g. over the counter Community or residential care e.g. Specialist nurses in pain clinics Tertiary care e.g. highly specialist services or hospital Other: Primary care e.g. used by GPs or practice nurses Emergency care e.g. paramedic services, trauma care Availability, launch or marketing dates, and licensing plans: Pregabalin is in phase III clinical trials. NHS or Government priority area: This topic is relevant to the Long-term (Neurological) Conditions National Service Framework (NSF) and the Musculoskeletal Services Framework (MSF), 2
Relevant guidance No relevant guidance identified. Clinical need and burden of disease Global population surveys estimate the prevalence of fibromyalgia between 0.7%-4.5% (equivalent to 273,000 to 1.76 million adults in England and Wales) 3. The incidence of fibromyalgia in primary care in the UK is estimated at 0.035% (14,700 people newly diagnosed each year) 4. The majority of people affected by fibromyalgia are women. In most cases, fibromyalgia develops between the ages of 30 and 60 years, but it can develop in people of any age, including children and the elderly 5. The cause of fibromyalgia is unknown, but may relate to serotonin and norepinephrine system dysfunction. Existing comparators and treatments Non-pharmaceutical management options for fibromyalgia include: exercise programmes, cognitive behavioural therapy (CBT), relaxation, acupuncture and patient support. Classes of drugs used off-label to manage fibromyalgia include: Anticonvulsants such as gabapentin or carbamazepine, to treat muscle spasms, anxiety and reduce pain; Low-dose tricyclic antidepressants such as amitryptyline, to reduce pain and aid sleep 6 ; Selective serotonin re-uptake inhibitors (SSRIs) such as fluoxetine; Analgesics and anti-inflammatory drugs such as paracetamol, non-steroidal antiinflammatory drugs (NSAIDs) and narcotic analgesics, to reduce pain; Local anaesthetic mixed with corticosteroids may also be injected into areas providing temporary pain relief. Efficacy and safety Trial name 81077 7 81059 Sponsor Pfizer Pfizer Status Abstract Abstract Location USA USA Design Randomised, double-blind, placebo- Randomised, double-blind, placebotrial. controlled, monotherapy trial. controlled Participants in N=750, > 18 years, 95% female, mean N=1051, >18 years, 93% female, trial age=50 yrs, median fibromyalgia 88% white, mean age=50 yrs, FMS syndrome (FMS) duration=10 yrs, duration=7.8 yrs, mean Visual baseline mean pain score=6.7. Patients Analogue Scale (VAS) pain score= 78 met American College of mm. Patients meet ACR criteria. Rheumatology (ACR) criteria. Randomised to placebo or pregabalin 300, 450 or 600 mg per day. Follow-up 14 weeks. 26 weeks. Outcomes Symptoms, pain, Patient Global Loss of therapeutic response (LTR): Improvement of Change (PGIC) & <30% reduction in VAS pain score. Key results safety Differences from placebo in mean change from baseline to endpoint in pain score for: 300, 450 and 600 mg were: 0.71, 0.98 and 1.00 respectively. PGIC for 300, 450 and 600 mg was: 68%, 78% and 66% respectively Pregabalin significantly delayed time to LTR: 25% LTR by day 7 for placebo, compared to day 34 for pregabalin. 174 (61%) of patients on placebo lost therapeutic response compared to 90 (32%) on pregabalin. 3
Major adverse effects compared to 48% placebo. Dizziness (35.8%) and somnolence (18.0%). Pregabalin was more effective than placebo for relieving pain and improving global assessment, functional status, sleep and fatigue. Dizziness, somnolence, sinusitis, arthralgia and anxiety. Trial name A0081057 9 Phase III extension. A0081078 10 Phase III. Sponsor Pfizer Pfizer Status Unp ublished, completed. Unpublished, completed. Location USA USA Design Non-randomised, open-label, Non-randomised, open-label, uncontrolled. uncontrolled. Participants in N=428, >18 years. Patients who N=500, >18 years. Patients met ACR trial participated in A0081056 (a non- criteria. randomised, open-label, uncontrolled trial). Follow-up 1-year open-label extension. 12 weeks. Primary outcome Long-term safety and tolerability. Safety. Expected reporting date Recruitment began in January 2005 with study completion in June 2006. Results not reported. Recruitment began in Feb 2006. Results not reported. Trial name A0081100 11 Phase III. A0081101 12 Phase III extension. Sponsor Pfizer Pfizer Status Ongoing Ongoing Location International International Design Randomised, double-blind, placebo controlled. Non-randomised, open-label, uncontrolled. Participants in N=740, >18. Patients meet ACR N=740, >18. Patients participated in trial criteria and score 40 mm on pain A0081100. (VAS). Follow-up 14 weeks. 12 weeks. Primary outcome Daily pain. Long-term safety and tolerability. Secondary Global evaluation, sleep, fatigue, - outcomes health-related quality of life, functioning, pain, mood disturbance. Expected reporting date Study began June 2006. Study began Dec 2006. E stimated cost and cost impact The cost per treatment period and relevant comparators is: Daily dose range Annual cost a Pregabalin 150-600 mg 840.00 Gabapentin 900-1800 mg 580.00 1161.00 Carbamazepine 400-1600 mg 40.00 190.00 Amitriptyline 25-75 mg 7.30 22.00 a BNF No. 53. March 2007. 4
Potential or intended impact speculative Patients Reduced morbidity Reduced mortality or increased Improved quality of life for survival patients and/or carers Quicker, earlier or more accurate Other: Non identified diagnosis or identification of disease Services Increased use Service reorganisation required Staff or training required Decreased use Other: Non identified C osts Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed New costs: Savings: Other: References 1 Wolfe F, Smythe HA, Yunus MB et al. The American College of Rheumatology 1990 Criteria for the classification of fibromyalgia: Report of the multicenter criteria committee. Arthritis & Rheumatism. 1990; 33 (2):160-172. 2 Turk DC, Robinson JP, Burwinkle T. Prevalence of fear of pain and activity in patients with fibromyalgia syndrome. The Journal of Pain. 2004; 5 (9):483-490. 3 White KP & Harth M. Classification, epidemiology and natural history of fibromyalgia. Current Pain & Headache Reports. 2001; 5:320-329. 4 Gallagher AM, Thomas JM. Hamilton WT et al. Incidence of fatigue symptoms and diagnoses presenting in UK primary care from 1990 to 2001. Journal of the Royal Society of Medicine 2004; 97:571-575. 5 NHS Direct online: www.nhsdirect.nhs.uk/articles. Accessed July 2007 6 Goldenberg DL, Burckhardt C, Crofford L. Management of fibromyalgia syndrome. Journal of the American Medical Association. 2004;292 (19): 2388-2395. 7 Arnold LM, Russell IJ, Duan WR et al. Pregabalin for management of fibromyalgia syndrome (FMS): a 14- week, randomised, double-blind, placebo-controlled, monotherapy trial. Presented at the 59 th Annual Scientific Meeting of the American Academy of Neurology, April 28 May 5, 2007, Boston 8 Crofford LJ, Simpson SL, Young JP et al. Fibromyalgia relapse evaluation and efficacy for durability of meaningful relief: (FREEDOM) trial: a six-month, double-blind, placebo-controlled trial of treatment with pregabalin. Presented at the 26 th Annual Scientific Meeting of the American Pain Society, May 2-5, 2007, Washington DC 9 ClinicalTrials.gov. A long-term, open-label, safety trial of pregabalin in patients with fibromyalgia. Available at: http://www.clinicaltrials.gov/ct/show/nct00151528?order=3 [Accessed: 04/07/07]. 10 ClinicalTrials.gov. A 12-week, open-label, safety trial of pregabalin in patients with fibromyalgia. Available at: http://www.clinicaltrials.gov/ct/show/nct00282997?order=5 [Accessed: 04/07/07]. 11 ClinicalTrials.gov. A 14-week, randomised, double-blind, placebo-controlled trial of pregabalin twice daily in patients with fibromyalgia. Available at: http://www.clinicaltrials.gov/ct/show/nct00333866?order=6 [Accessed: 04/07/07]. 12 ClinicalTrials.gov. A 12-week, open-label, safety trial of pregabalin in patients with fibromyalgia. Available at: http://www.clinicaltrials.gov/ct/show/nct00346034?order=4 [Accessed: 04/07/07]. 5
The National Institute for Health Research Research Programme is funded by the Department of Health. The views expressed in this publication are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health The, Department of Public Health and Epidemiology University of Birmingham, Edgbaston, Birmingham, B15 2TT, England Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269 www.pcpoh.bham.ac.uk/publichealth/horizon 6