Fibromialgia y Pregabalina

ADIS DRUG EVALUATION
Drugs 2008; 68 (15): 2205-2223 0012-6667/08/0015-2205/$53.45/0 2008 Adis Data Information BV. All rights reserved.
Pregabalin
A Review of its Use in Fibromyalgia
Katherine A. Lyseng-Williamson and M. Asif A. Siddiqui
Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Conshohocken, Pennsylvania, USA
Various sections of the manuscript reviewed by: F. Blotman, Rheumatology Department, University Hospital of Montpellier, Montpellier, France; S.F. Carville, UK Age Research Forum, London, United Kingdom; E. Diri, University of North Dakota, Trinity Health Center, Minot, North Dakota, USA; K.. Forseth, Department of Rheumatology, National Hospital, Oslo, Norway; M.J. Puszczewicz, Department of Rheumatology, Rehabilitation and Internal Medicine, Poland. University of Medical Sciences, Poznan,
Data Selection Sources: Medical literature published in any language since 1980 on pregabalin, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug. Search strategy: MEDLINE, EMBASE and AdisBase search terms were pregabalin and fibromyalgia. Searches were last updated 8 September 2008. Selection: Studies in patients with fibromyalgia who received pregabalin. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included. Index terms: Fibromyalgia, pregabalin, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.
Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2206 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2207 2. Pharmacological Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2208 2.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2208 2.2 Other Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2208 2.3 Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2209 2.4 Potential Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2210 3. Therapeutic Efficacy in Fibromyalgia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2210 3.1 Short-Term Fixed-Dosage Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2211 3.1.1 Primary Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2211 3.1.2 Secondary Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2214 3.2 Durability-of-Response (FREEDOM) Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2215 3.2.1 Time to Loss of Therapeutic Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2216 4. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2217 5. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2219 6. Place of Pregabalin in the Management of Fibromyalgia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2220
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Lyseng-Williamson & Siddiqui
Summary
Abstract
Oral pregabalin, a calcium channel 2-subunit ligand with analgesic, anxiolytic and antiepileptic activity, has shown efficacy in the treatment of fibromyalgia. It has a multidimensional effect in the treatment of this complex condition, and is associated with rapid and clinically significant improvements in several outcome measures relating to core symptoms of the syndrome, including pain and sleep, in patients with long-standing fibromyalgia. Pregabalin treatment is also associated with improvements in the overall health status of these patients. The beneficial effects of pregabalin are durable in patients with an initial response to the drug. The most common adverse events associated with the drug are dizziness and somnolence, which are generally mild to moderate in intensity and are tolerated by many patients. Pregabalin is, therefore, a valuable option in the first-line treatment of patients with fibromyalgia. Pregabalin selectively binds with high affinity to the 2 subunit of voltage-gated calcium channels, which are widely distributed throughout the central and peripheral nervous systems. This modulates calcium influx in presynaptic nerve terminals to reduce excessive release of several excitatory neurotransmitters. Pregabalin demonstrates beneficial effects on the key symptoms and co-morbidities associated with fibromyalgia (i.e. pain, anxiety and sleep). Oral pregabalin is absorbed rapidly (peak plasma concentrations occur within 1.5 hours) and exposure is dose proportional. Metabolism of pregabalin is negligible, with most of the drug being excreted unchanged in the urine. In healthy volunteers, the mean apparent elimination half-life is 6.3 hours. Clearance of pregabalin is directly related to creatinine clearance; dosage adjustments are required in patients with impaired renal function. Oral pregabalin was generally associated with improvements from baseline in mean pain scores in short-term, randomized, double-blind, placebo-controlled, multicentre trials in patients with fibromyalgia. In three 8-, 13- or 14-week trials conducted in the US, relative to placebo recipients, pregabalin 450 or 600 mg/day recipients demonstrated significant improvements from baseline in endpoint mean pain numerical rating scale (NRS) scores (primary endpoint), with pregabalin 300 mg/day recipients also showing significant improvements in two of the trials. Mean pain NRS scores for all pregabalin arms were significantly different from those with placebo as early as week 1, with significant improvements generally sustained through most or all weeks of the treatment period in the pregabalin 300, 450 and 600 mg/day arms. Improvements from baseline in Fibromyalgia Impact Questionnaire (additional co-primary endpoint) total scores in the pregabalin 450 and 600 mg/day groups were significantly better than those in the placebo groups in the 14-week trial, but there was no significant difference between placebo and any of the pregabalin groups in the 13-week trial. Patient-rated overall status, as assessed by response on the Patient Global Impression of Change scale (additional co-primary endpoint), improved in patients with fibromyalgia receiving pregabalin 300, 450 or 600 mg/day in the 13- and 14-week US trials. Relative to placebo, pregabalin 300, 450 and 600 mg/day was associated with improvements in several sleep parameters in the short-term trials. Significant
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Pharmacological Properties
Therapeutic Efficacy
2008 Adis Data Information BV. All rights reserved.
Pregabalin: A Review
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differences between pregabalin and placebo were reported for only some of the other secondary endpoints and were generally not consistent across trials. Continued treatment with pregabalin was effective in prolonging the efficacy of open-label pregabalin in patients with fibromyalgia who had shown initial response to open-label pregabalin. In the FREEDOM trial, patients who had an initial response to pregabalin during a 6-week open-label phase were randomized to a further 26 weeks of treatment with their optimized dosage of pregabalin or placebo. Based on Kaplan-Meier estimates, the time to loss of therapeutic response was significantly longer in the pregabalin 300600 mg/day group than in the placebo group. Sensitivity analyses, which tested the validity of the primary assumptions, confirmed the superiority of pregabalin over placebo.
Tolerability
The tolerability profile of pregabalin in patients with fibromyalgia is consistent with the known adverse effects the drug. Although adverse events were frequently reported in the pregabalin and placebo groups in clinical trials in patients with fibromyalgia, most events were of mild to moderate intensity and were often of limited duration. The treatment-emergent adverse events most frequently associated with pregabalin were dizziness and somnolence. These events were generally reported shortly after the initiation of pregabalin therapy, were mild to moderate in intensity and occurred more frequently at higher dosages, but led to discontinuation of pregabalin therapy in only some patients.
1. Introduction Fibromyalgia is a complex, idiopathic nonprogressive clinical pain syndrome[1-5] that affects 24% of the general population in the US and is predominantly seen in women.[5] The onset of symptoms typically occurs at 2050 years of age, but may present at any age.[4] Because of the lack of objective diagnostic markers, muscle pain and tenderness (the defining characteristics of fibromyalgia) are used to distinguish the condition from other rheumatic disorders.[5] Although their use as a diagnostic tool in clinical practice has been the subject of some debate,[6,7] the 1990 American College of Rheumatology (ACR) classification criteria,[8] which were intended to standardize research studies, define fibromyalgia as widespread aching pain for at least 3 months and hyperalgesia at a minimum of 11 of the 18 specified muscle-tendon sites. Among the possible accompanying symptoms are fatigue, sleep disturbances, headache, morning stiffness, subjective swollen joint feeling, paraesthesia, autonomic symptoms
(e.g. irritable bowel and bladder syndromes), temporomandibular joint syndrome, restless legs syndrome and psychological disturbances (e.g. depression, anxiety, and memory and cognitive problems.).[1,4,6,9,10] Inflammation is not associated with fibromyalgia.[5] The pain and other symptoms of fibromyalgia vary in intensity, and relapse and remit over time.[4,10] Although the aetiopathological processes of fibromyalgia are unclear and no widely accepted model of the disorder currently exists, the syndrome appears likely to be a dysfunction of pain-modulatory systems within the CNS.[9,11] Neurobiological studies indicate that fibromyalgia-related pain may involve augmented central pain processing, resulting in patients experiencing pain without appropriate peripheral nociceptive input.[6,9,11] Pain and other features of fibromyalgia may involve dysfunction of the autonomic nervous system and the hypothalamic-pituitary adrenal axis.[10,11] Genetic, environmental (e.g. co-morbid disease, infections or physical trauma) and psychological (e.g. somatization, anxiety, and personal or family history of depresDrugs 2008; 68 (15)
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sion) factors may contribute to the development of the disease.[1,6,12] As there is no known cure for fibromyalgia, pharmacological and nonpharmacological therapy (e.g. exercise, cognitive behavioural therapy and patient education) are recommended to help reduce pain and treat other symptoms.[1-3] In the past, drug therapy was mostly based on empirical research; however, the US FDA has approved two oral agents for the treatment of fibromyalgia. The first agent to be approved was pregabalin (Lyrica 1),[13] which has been followed by the more recent approval of duloxetine.[14] This article provides a review of the pharmacology, therapeutic efficacy and tolerability of oral pregabalin in patients with fibromyalgia. A discussion of the use of pregabalin in other indications approved in the US[15] or EU[16] (adjunctive therapy for partial onset seizures [US[15] and EU[16]], neuropathic pain associated with diabetic peripheral neuropathy [US],[15] postherpetic neuralgia [US],[15] generalized anxiety disorder [EU],[16] and peripheral and central neuropathic pain [EU][16]) is beyond the scope of this article. 2. Pharmacological Properties Pregabalin is associated with analgesic, anxiolytic and antiepileptic activity.[17-25] This section provides a summary of the pharmacological properties of pregabalin that may be important to its efficacy in the treatment of fibromyalgia based on data from previous reviews,[17-25] studies in animals,[26-29] healthy volunteers[30,31] or patients,[32] the manufacturers prescribing information[15] and pharmacokinetic studies.[33-35] Some studies are available as abstracts.[27,33,34] The effect of pregabalin on pain, sleep and other parameters in patients with fibromyalgia is discussed in section 3.
2.1 Mechanism of Action
(S) H2N HO2C
Fig. 1. Chemical structure of pregabalin
site as gabapentin; the two agents have similar, but not identical, pharmacological profiles.[11,18-20] In vitro, pregabalin selectively binds with high affinity to the 2 subunit of voltage-gated calcium channels, which are widely distributed throughout the central and peripheral nervous systems.[20] The subsequent attenuation of Ca2+ ion influx at presynaptic nerve endings appears to modulate the excessive release of several excitatory neurotransmitters, including glutamate, norepinephrine (noradrenaline), substance P and calcitonin gene-related peptide.[22,23] A study in mice with a mutation of the 2-1 subunit protein of voltage-gated calcium channels confirmed that the analgesic effects of pregabalin are mediated through binding to the 2-1 subunit.[26] Although pregabalin is a structural derivative of the inhibitory neurotransmitter GABA, it does not interact with GABAA, GABAB or benzodiazepine receptors, alter rat brain GABA levels or augment GABAA responses in cultured neurons.[15,19,21] While pregabalin does not acutely inhibit GABA reuptake, with prolonged exposure to cultured neurons, it produces a paradoxical enhancement of GABA uptake by increasing the redistribution of GABA-transporter protein to the cell surface.[15] Pregabalin does not block sodium channels, inhibit dopamine, serotonin or norepinephrine reuptake, have activity at opioid, serotonin or dopamine receptors, or alter cycloxygenase enzyme activity.[15]
2.2 Other Pharmacodynamic Properties
Pregabalin is the pharmacologically active Setantiomer of 3-aminomethyl-5-methyl-hexanoic acid (figure 1).[15] It interacts with the same binding
1
Pregabalin demonstrated beneficial effects on the key symptoms and co-morbidities associated with fibromyalgia (i.e. pain, anxiety and sleep) in animal models.[17,18,26-29] Pregabalin dose-dependently inhibited capsaicin-induced allodynia,[27] produced anxiolytic-like effects[28] and increased slow-wave
The use of trade names is for product identification purposes only and does not imply endorsement.
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sleep in rodent models.[29] Pregabalin has also demonstrated antiallodynic and antihyperalgesic activities in a number of other rodent models of pain (including mechanical allodynia induced by vincristine, streptozocin, nerve injury or surgery, and hyperalgesia induced by formalin, carrageenan, substance P, NMDA and thermal injury).[17] The antiallodynic and antihyperalgesic effects of pregabalin were observed at dosages that were one-quarter to one-half of those of gabapentin.[18] Pregabalin did not generally impair cognitive and psychomotor function[30] and modestly improved some measures of sleep architecture and sleep[31] in a randomized, double-blind, placebo-controlled crossover study in 24 healthy volunteers. In assessments of cognitive and psychomotor function using a validated test battery, pregabalin 450 mg/day did not significantly impair reaction time, vigilance or serial memory scanning relative to placebo, but was associated with transient minor impairment of CNS arousal, divided attention and sedation (all p < 0.05), and modestly improved brake reaction time (p < 0.05).[30] Relative to placebo, pregabalin 450 mg/day was associated with small, but significant (p < 0.05), improvements in slow-wave (stage 3/4) sleep and time to sleep-onset latency, but a significantly lower proportion of rapid-eye-movement sleep during the total sleep period in the crossover study.[31] Moreover, in an exploratory 4-week, randomized, doubleblind study in 15 epileptic patients with clinically relevant sleep disturbance, pregabalin was associated with improvements in sleep continuity relative to placebo that appeared to be independent of seizure control.[32]
2.3 Pharmacokinetic Properties
The pharmacokinetics of pregabalin in patients with fibromyalgia have not been investigated; therefore, data in healthy volunteers administered single or repeated doses of pregabalin are reported, unless otherwise indicated. Oral pregabalin is absorbed rapidly (peak plasma concentrations occur within 1.5 hours), and exposure to single (25300 mg/day) or multiple dosages
(75900 mg/day) is dose proportional.[15] After a single dose of pregabalin 300 mg, mean values for peak plasma concentration and area under the plasma concentration-time curve were 9.46 g/mL and 66.3 g h/mL.[33] Steady-state concentrations are reached within 2448 hours following administration of multiple doses of pregabalin.[15] The oral bioavailability of pregabalin is high (90%) and independent of dose.[15] Although administering pregabalin with food delays the rate of absorption of the drug, it does not affect the extent of its absorption.[15] Pregabalin is not bound to plasma proteins and has an apparent volume of distribution of 0.5 L/ kg.[15] Pregabalin, which is a substrate of the system L transporter that transports large amino acids across the brain and gut, crossed the blood-brain barrier in preclinical animal studies;[15,25] however, studies of such transport in humans are currently lacking.[15] Metabolism of pregabalin is negligible, with most of the drug being excreted unchanged in the urine.[15,34] In healthy volunteers, 90% of a radiolabelled 100 mg dose of pregabalin was excreted in the urine as unchanged drug and only 0.9% was accounted for by the major metabolite of pregabalin (the N-methylated derivative).[34] Less than 0.1% of the dose was recovered in the faeces.[34] In healthy volunteers with normal renal function, the mean elimination half-life (t1/2) was 6.3 hours and was independent of dose.[15] Mean values for renal clearance of pregabalin in young healthy volunteers (67.080.9 mL/min), together with the lack of plasma protein binding of the drug, indicate that renal tubular reabsorption is involved in pregabalin clearance.[15] Clearance of pregabalin is directly related to creatinine clearance (CLCR).[35] In a study in 38 patients with various degrees of renal impairment (including 12 undergoing haemodialysis),[35] exposure to pregabalin increased with decreasing renal function and pregabalin was highly cleared by haemodialysis. Dosage adjustments are, therefore, necessary in patients with impaired renal function or those undergoing haemodialysis (section 5).[15] Clearance of preDrugs 2008; 68 (15)
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gabalin is not affected by sex or race, but is decreased in the elderly, which is consistent with agerelated changes in renal function.[15]
2.4 Potential Drug Interactions
Pregabalin has not been, and is unlikely to be, associated with any pharmacokinetic drug interactions.[15,20,24,25] As pregabalin does not undergo hepatic metabolism and does not induce or inhibit cytochrome P450 (CYP) enzyme systems in vitro, it is not anticipated that it will interact with CYP1A2 and CYP3A4 substrates.[15] In pharmacokinetic analyses in healthy volunteers and various patient populations, the pharmacokinetics of pregabalin were not significantly affected by concomitant administration of lorazepam, oxycodone, alcohol, antihyperglycaemics (glibenclamide [glyburide], insulin and metformin), furosemide (frusemide) and numerous anticonvulsants.[15] Pregabalin did not have any effect on the pharmacokinetics of an oral contraceptive (norethisterone [norethindrone]/ethinylestradiol 1 g/35 g), lorazepam, oxycodone, alcohol and numerous anticonvulsants.[15] Concomitant administration of pregabalin with oxycodone, lorazepam or alcohol (ethanol) had an additive pharmacodynamic effect on cognitive and gross motor functioning, but not on respiration.[15] 3. Therapeutic Efficacy in Fibromyalgia The therapeutic efficacy of pregabalin monotherapy in the treatment of adults with fibromyalgia has been evaluated in several randomized, double-blind, placebo-controlled, multicentre trials.[36-40] This section focuses on the results of fully published trials conducted in the US, including three short-term (duration of 8,[36] 13[37] or 14[38] weeks) trials (n = 529748; section 3.1), and the longer durability-of-response FREEDOM (Fibromyalgia relapse evaluation and efficacy for durability of meaningful relief) trial (n = 566; section 3.2).[40] Preliminary results (i.e. currently available as an abstract[41] or abstracts plus posters[39,42,43]) of an international 14-week trial conducted in countries other than the US (Europe, Asia, Australia, Canada, Mexico and
South America; n = 735),[39] pooled analyses of the three short-term US trials,[42,43] and a 1-year openlabel extension study of the 13-week trial[41] are also briefly discussed. The total daily dose of oral pregabalin (administered as two divided doses in most trials[37-40] and three divided doses in one trial[36]) is reported. For inclusion in the placebo-controlled trials,[36-40] patients aged 18 years were required to meet the 1990 ACR criteria for fibromyalgia (i.e. widespread pain for 3 months and pain in 11 of 18 specific tender points) and have a baseline pain visual analogue scale (VAS) score 40 mm on a scale of 0100 mm. In the 8- to 14-week trials,[36-38] patients were also required to have mean daily diary pain numerical rating scale (NRS) scores 4 on a scale of 010 during the week before randomization.[36-39] Among exclusion criteria were evidence of inflammatory or rheumatological disease, other severe painful disorders, clinically significant or unstable medical or psychiatric disorders, and a calculated CLCR 60 mL/min.[36-40] The 8-week trial excluded patients in whom fibromyalgia-related pain had not responded to treatment with gabapentin 1.2 g/ day.[36] Patients could not receive other medications for the treatment of fibromyalgia or its associated co-morbidities (e.g. antidepressants, anticonvulsants, most analgesics, hypnotics, sedatives or other agents),[36-40] but, where stated, were permitted to receive 4 g/day of paracetamol (acetaminophen) as rescue medication for pain,[36-38,40] 325 mg/day of aspirin (acetylsalicylic acid) for cardiac prophylaxis[36-38] and stable nonpharmacological therapy.[36-38] Baseline patient characteristics and demographics were not significantly different between randomized treatment groups in any of the trials.[36-40] Across treatment arms in all trials,[36-40] the mean duration of fibromyalgia was 711 years, the mean patient age was 4851 years and the majority (9196%) of patients were women. In the US trials, most (8895%) of the patients in each treatment arm were White,[36-40] whereas 75% of patients were White in the international trial.[39]
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Table I. Overview of selected assessment tools used to evaluate the clinical effectiveness of oral pregabalin in short-term (8- to 14-wk), randomized, placebo-controlled, clinical trials in patients (pts) with fibromyalgia[36-39] Assessment method Pain NRS scorea Description/comments Assesses pain on an 11-point scale (010) Rating of pain during the previous 24 h reported in pt diary on awakening each day A 30% reduction in pain NRS score is considered clinically meaningful[44] Primary or co-primary endpoints
Fibromyalgia Impact Pt-rated instrument with 10 subscales (physical functioning, no. of days per wk pt felt well; no. of days per Questionnaire total scoreb wk pts unable to work [including housework] because of fibromyalgia symptoms; work difficulty; pain; fatigue; morning tiredness; stiffness; anxiety; and depression), each rated on a scale of 010, which are combined for a total score of 0100 A 1-point change in subscale scores has been suggested to represent a clinically meaningful difference[45] Pt Global Impression of Changeb,c Pt-rated instrument that measures changes in overall health status on a scale of 1 (very much improved) to 7 (very much worse) Allows pts to assess improvement or worsening of pain, other symptoms, functioning and adverse effects
Secondary sleep endpoints Sleep quality NRS score Medical Outcome StudySleep scale scores a b c Assesses sleep quality on an 11-point scale (010) Rating of sleep quality reported in pt diary each day Assesses multiple aspects of pts sleep profile and overall sleep problems on seven subscales (sleep disturbance; snoring; awaken short of breath or with a headache; quantity of sleep; optimal sleep, sleep adequacy; and somnolence) plus a 9-item overall sleep problem index, each rated on a scale of 0100
Primary[36] or co-primary[37-39] endpoint was the mean change from baseline at endpoint (based on the mean pain NRS score for the last 7 d the pt was receiving study medication). Additional co-primary endpoint that was used only if a significant between-group difference in mean pain NRS score was achieved.[37,38] Co-primary endpoint.[39]
NRS = numerical rating scale.
3.1 Short-Term Fixed-Dosage Trials
The 8-week trial evaluated the efficacy of pregabalin 150, 300 or 450 mg/day versus placebo; patients randomized to the 450 mg/day dosage received 300 mg/day for the first 3 days, followed by 450 mg/day thereafter.[36] In the 13-[37] or 14week[38,39] trials, patients were randomized to treatment with pregabalin 300, 450 or 600 mg/day or placebo; a 1-week single-blinded, placebo run-in phase was followed by a 1-[37] or 2-week[38,39] double-blind, dosage-escalation period and then by 12 weeks of double-blind fixed-dosage treatment. All trials had a 1-week follow-up phase.[36-39] In the 14-week studies, patients who responded to placebo (i.e. those with 30% decrease in pain VAS) in the initial 1-week run-in phase were not randomized into subsequent phases of the trials.[38,39] At baseline, mean pain NRS scores across treatment arms were 6.67.3.[36-39] A number of primary and secondary efficacy endpoints related to the symptoms of fibromyalgia
were assessed in each trial (see table I for a description of selected key endpoints).[36-39] Analyses were performed on the intent-to-treat (ITT) population (defined as all randomized patients who received at least one dose of study medication, using the last-observation-carried-forward method.[36-39] Where applicable, endpoints were analysed using ANCOVA models and adjustment for multiple comparisons was made based on Hochbergs procedures.[36-39] Patient Global Impression of Change (PGIC) responses and proportions of responders were analysed using the CochranMantel-Haenszel procedure, with adjustment for centre.[36-39]
3.1.1 Primary Endpoints
Pregabalin treatment was generally associated with improvements (i.e. decrease) from baseline in mean pain scores.[36-39] In the US trials, relative to patients receiving placebo, recipients of pregabalin 450 or 600 mg/day demonstrated significant improvements from baseline in endpoint mean pain
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NRS scores,[36-38] with recipients of pregabalin 300 mg/day also showing significant improvements in two of the trials[37,38] (table II). In preliminary results of the international trial, mean changes from baseline in mean pain NRS scores were significantly different between pregabalin 450 mg/day and placebo recipients (between-group difference 0.54; p = 0.02), but not between pregabalin 300 or 600 mg/day and placebo recipients (between-group differences 0.34 and 0.23).[39] In all trials, mean pain NRS scores for all pregabalin arms were significantly different from those for the placebo arms as early as week 1,[36-39] with significant improvements generally sustained through most or all weeks of the treatment period in the pregabalin 300,[37,38] 450[36-39] and 600[37-39] mg/ day arms. In a pooled analysis of the endpoint results of the three US trials (n = 2013),[42] pregabalin 300, 450 and 600 mg/day were associated with significant (p < 0.001) and clinically relevant improvements from baseline in mean pain NRS scores relative to placebo. The proportion of patients who responded to treatment (defined as a 30% or 50% decrease in mean pain NRS score) was significantly (p < 0.05) higher in some pregabalin (300,[38] 450[36,38] or 600[38] mg/day) arms than in the placebo arms in two trials,[36,38] but between-group differences were not significant for any pregabalin dosage in the other trial[37] (table II). As the first co-primary endpoint (significant between-group difference in mean pain NRS score) was met in the 13-[37] and 14-week[38] US trials, two additional co-primary endpoints (changes from baseline in Fibromyalgia Impact Questionnaire [FIQ] total scores at endpoint and PGIC at the termination visit) were assessed. Improvements in FIQ total scores in the pregabalin 450 and 600 mg/ day groups were significantly better than those in the placebo groups in one trial,[38] but there was no significant difference between placebo and any of the pregabalin groups in the other trial[37] (table II). In the international trial, differences between the pregabalin and placebo arms in the mean improvement from baseline in FIQ total score were signif 2008 Adis Data Information BV. All rights reserved.
icant for the pregabalin 450 mg/day arm (betweengroup difference 5.87; p = 0.001), but not for the pregabalin 300 and 600 mg/day arms (numerical data not reported).[39] Patient-rated overall status, as assessed by PGIC response, generally improved in patients with fibromyalgia receiving pregabalin.[37-39] In both US trials,[37,38] significant (p < 0.05) differences in the PGIC response favouring pregabalin over placebo were shown for the pregabalin 300, 450 or 600 mg/ day treatment groups (figure 2). In the international trial,[39] significant (p 0.05) between-group differences in the proportion of patients with improved overall PGIC status (co-primary endpoint) were shown with pregabalin 450 mg/day (73%) and 600 mg/day (69%) versus placebo (56%), but not with pregabalin 300 mg/day (67%). The association between either changes in pain or PGIC response and changes in other endpoints was considered in an exploratory analysis[42] based on pooled results of the three US trials.[36-38] Changes in mean pain NRS scores were highly correlated with changes in mean sleep quality NRS scores and moderately correlated with changes in fatigue (as assessed by Multidimensional Assessment of Fatigue [MAF] scores), but showed little correlation with mood, anxiety and/or depressive symptoms (as assessed by Hospital Anxiety and Depression Scale [HADS]-Depression [HADS-D] and HADS-Anxiety [HADS-A] subscale scores).[42] Pain improvement had the greatest impact on the likelihood of a patient being a PGIC responder, followed by the improvement in sleep quality. Fatigue had only an intermediate impact and the predicted impact of mood, anxiety and/or depressive symptoms appeared quite modest.[42] Moreover, a post hoc analysis based on pooled data[43] from the three US trials[36-38] suggests that pregabalin reduces pain in patients with or without symptoms of anxiety or depression. Although 38% of patients had moderate to severe anxiety and 27% had moderate to severe depression (HADS-A or HADS-D score 11 on scales of 021) at baseline, pain improved significantly with pregabalin
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Table II. Efficacy of oral pregabalin (PRE) in the treatment of fibromyalgia. Results of primary and selected secondary sleep endpoints in three short-term (8- to 14-wk), randomized, double-blind, placebo (PL)-controlled, multicentre trials in patients (pts) with fibromyalgia conducted in the US.[36-38] Values are least-square means analysed using ANCOVA models, with adjustment for multiple comparisons based on Hochbergs procedures. A decrease in score indicates an improvement (see table I for a description of the endpoints). The total daily dosage of PRE (150450[36] or 150600[37,38] mg/d) was administered in two[37,38] or three[36] divided doses 8-wk trial[36] PRE 150 PRE 300 PRE 450 PL 131 5.74 NR NS 31 13 19 29** 13 24* 27** 38 48** 27 43 43 44 35 42* 50*** NS 0.43* 0.47* 0.66** 0.71*** 0.98*** 48*** 30*** NR NR NR 0.93*** 1.00*** 30 15 5.47 4.94 5.88 5.26 1.84 5.23 1.87 5.04 2.06 5.70 1.40 4.93 1.75 4.66 2.03 4.64 2.05 132 128 129 185 183 190 190 183 190 188 184 5.64 1.04 PRE 300 PRE 450 PRE 600 PL PRE 300 PRE 450 PRE 600 PL 13-wk trial[37] 14-wk trial[38]
Endpoint
Mean pain numerical rating scale score (primary[36] or co-primary[37,38] endpoint)a,b
No. of pts evaluated
Score at endpoint
Change from baseline
Treatment difference (PRE vs PL)
Percentage of pts with 30% decrease in score
Percentage of pts with 50% decrease in score
Fibromyalgia Impact Questionnaire total score (co-primary endpoint[37,38])c 185 48.18 16.15 2.48 endpoint)[36-38]b,d 128 3.99 NR 0.86*** endpoint)[36-38]e 180185f 178183f 185189f 183190f 183 45.90 NR S* 44.59 NR S** 45.51 NR S* 50.71 NR 46.89 11.39 4.74* 185 45.43 12.85 6.20** 188 43.19 15.09 8.44*** 180 51.63 6.65 0.97*** NR 1.3*** 5.30 4.54 2.19 4.44 2.29 4.20 2.53 1.21*** 129 185 183 190 190 5.41 1.32 183 4.33 1.90 0.74*** 190 3.96 2.28 1.12*** 188 3.73 2.51 1.35*** 184 5.07 1.16 2.05 1.21 48.62 15.71 49.45 14.88 50.66 13.66 183 190 190 183 49.03 10.70 2.96 190 46.75 12.98 5.24** 188 46.65 13.08 5.34** 184 51.99 7.74
Score at endpoint
Mean sleep quality numerical rating scale score (secondary 131 4.91 NR NS NR 0.6* 4.68 132
Score at endpoint
Medical Outcomes Study (MOS)-Sleep overall sleep problems index (secondary 123 45.66 NR NR 8.5*** NR 8.9*** NR 13.7*** 45.26 40.44 54.16 123 122 121
Score at endpoint
Mean value at baselines 7.0 for all pts included in this analysis (n = 520),[36] and 7.1 (n = 748)[37] and 6.66.8 (n = 745)[38] for all randomized pts.
Mean scores derived from the daily diary ratings of the last 7 d that pts received the study medication.
Mean value at baseline in all randomized pts 64.3 (n = 748)[37] and 58.761.1 (n = 745).[38]
Mean value at baseline 6.6 for all pts included in this analysis (n = 489),[36] and 6.7 (n = 748)[37] and 6.16.4 (n = 745) for all randomized pts.
Mean value at baseline 62.5 for all pts included in this analysis (n = 489),[36] 65.0 for all randomized pts with a baseline evaluation (n = 741)[37] and 56.760.4 for all randomized pts (n = 745).[38]
Different numbers of pts were available for assessment of individual items of the Medical Outcomes Study-Sleep Scale; specific pt numbers were not reported for this parameter.
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NR = not reported; NS = not significant (numerical value NR); S = significant (numerical value NR); * p < 0.05, ** p < 0.01, *** p 0.001 vs PL.
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a 11%
Any worsening No change Any improvement
17% 12% 71% 72%
18% 10% 69%
23% 20% 56% 21%
PRE 300 (n = 175) b
PRE 450 (n = 173)
PRE 600 (n = 175)
PL (n = 178)
18% 14% 68% 77%
12% 11%
18% 16% 66% 47%
22%
31%
PRE 300 (n = 183)
PRE 450 (n =190)
PRE 600 (n = 188)
PL (n = 184)
Fig. 2. Effect of oral pregabalin (PRE) on the overall status of patients (pts) with fibromyalgia. Proportion of pts reporting any improvement (minimally, much or very much improved), no change or any worsening (minimally, much or very much worse) in overall status using the Pt Global Impression of Change (PGIC) assessment tool in two randomized, double-blind, placebo-controlled, multicentre trials (co-primary endpoint). Pts received PRE 300, 450 or 600 mg/d or placebo (PL) in two divided doses for (a) 13 wk[37] or (b) 14 wk.[38] Significant (p 0.05) differences in the PGIC response favouring PRE over PL were observed for across all three PRE groups in both trials.
treatment regardless of whether patients had baseline anxiety or depressive symptoms.[43]

3.1.2 Secondary Endpoints
Pregabalin was associated with improvements in sleep.[36-39] In secondary analyses of the effect of pregabalin on sleep in the US trials, patients receiving pregabalin 300, 450 and 600 mg/day showed significant (p < 0.05) improvements in sleep quality (as measured by the decrease from baseline in mean sleep quality NRS scores) relative to patients receiving placebo (table II).[36-38] In addition, where reported, pregabalin 300, 450 and 600 mg/day recipients had significant (p < 0.05) improvements from baseline relative to placebo recipients with regard to several parameters measured by the Medical Outcomes Study (MOS)-Sleep scale (overall sleep problems index [table II],[36-38] sleep disturbance,[37,39] sleep adequacy [300 and 450 mg/day only],[37] sleep quantity[37] and sleep quality[38]). However, recipients of pregabalin 450 and 600 mg/ day had significantly (p < 0.05) greater increases
from baseline in MOS-Sleep somnolence subscale scores than placebo recipients.[37] Somnolence is a commonly reported adverse event in clinical trials of pregabalin (see section 4). Only some of the other secondary endpoints showed significant differences in changes from baseline in patients receiving pregabalin relative to those receiving placebo in the US trials (table III). Any significant between-group differences in these parameters were usually shown in the recipients of the higher pregabalin dosages and were often not consistently displayed across trials (table III). The efficacy of long-term treatment with pregabalin has been shown in preliminary results of a 1year open-label extension[41] of the 13-week doubleblind US trial in patients with fibromyalgia.[37] Of the 429 patients who entered the study, 249 (58%) completed the study (median duration of pregabalin treatment 357 days).[41] Pregabalin 150600 mg/day was associated with improvements from baseline in pain as assessed by Short-Form McGill Pain QuesDrugs 2008; 68 (15)
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tionnaire pain VAS scores and total pain, sensory pain, affective pain and present pain intensity domain scores.[41]
3.2 Durability-of-Response (FREEDOM) Trial
at both of two timepoints (week 4 or 5 and week 6) of the open-label phase.[40] The primary efficacy endpoint was the difference between all pregabalin and all placebo recipients in the time to loss of therapeutic response (defined as either a <30% reduction in pain VAS score relative to the baseline value in the open-label phase at two consecutive visits, or worsening of fibromyalgia symptoms necessitating alternate treatment in the judgement of the investigator) using Kaplan-Meier time-to-event analysis and log-rank statistical comparisons.[40] Treatment was discontinued in patients who met either criterion for loss of therapeutic response. Kaplan-Meier analysis was also used to compare the relative efficacy of pregabalin and placebo with regard to a number of secondary endpoints. Analyses were performed on the ITT population (defined as all patients who were randomized at the end of the open-label phase).[40] In the primary analysis, patients who completed the double-blind phase, withdrew prior to loss of therapeutic response
In the FREEDOM trial,[40] a 6-week open-label treatment phase determined the optimal dosage of pregabalin in each patient (the initial dosage of 150 mg/day was titrated to 300, 450 or 600 mg/day based on pain control and tolerability). This was followed by a 26-week double-blind treatment phase, in which only those patients who had a response to pregabalin during the open-label phase were randomized to a further 26 weeks of treatment with their optimized dosage of pregabalin or placebo. In the placebo group, pregabalin treatment was tapered off during the first week of the double-blind phase in a blinded manner. Response was defined as a 50% reduction from baseline in pain VAS score plus a rating of overall improvement on the PGIC scale of much improved or very much improved
Table III. Efficacy of oral pregabalin (PRE) in treating fibromyalgia with regard to secondary endpoints. Overview of results of selected secondary endpoints in 8-,[36] 13-[37] or 14-wk[38] randomized, double-blind, placebo (PL)-controlled, multicentre trials of PRE in patients with fibromyalgia conducted in the US[36-38] and a pooled analysis of these trials (available as an abstract plus poster)[42] Treatment difference (PRE 150, 300 or 450 mg/d vs PL[36] or PRE 300, 450 or 600 mg/d vs PL[37,38])a HADS-Anxiety score NS,[36-38] with the exception of PRE 600 mg/d in the 14-wk trial[38] and PRE 450 and 600 mg/d in the pooled data[42] HADS-Depression score NS,[36-38] with the exception of PRE 450 mg/d in the pooled data[42] Multidimensional Assessment of Fatigue global fatigue index score NS,[36-38] with the exception of PRE 300 and 450 mg/d in the 8-wk trial,[36] and PRE 300, 450 and 600 mg/d in the pooled data[42] Short-Form McGill Pain Questionnaire domain scores Pain visual analogue scale scores and total pain, sensory pain, affective pain and domain scores: NS,[36,37] with the exception of PRE 450 mg/d in the 8-wk trial[36] Present pain intensity domain score: NS[36,37] Short-Form 36 Health Survey domain scores Physical functioning, physical role limitations and emotional role limitations domain[36-38] or physical component[38] scores: NS Social functioning domain score: NS, with the exception of PRE 450 mg/d in the 8-[36] and 14-wk[38] trials Bodily pain domain score: NS,[36-38] with the exception of PRE 450 mg/d in the 8-wk trial[36] Mental health domain[36-38] and mental component[38] scores: NS,[36-38] with the exception of PRE 600 mg/d in the 14-wk trial[38] Vitality domain score: NS,[36-38] with the exception of PRE 450 in the 8-wk trial[36] and PRE 450 and 600 mg/d in the 14-wk trial[38] General health perception domain score: NS,[36-38] with the exception of PRE 150, 300 and 450 mg/d in the 8-wk trial[36] Other Manual Tender Point Survey Fibromyalgia syndrome intensity,[36] Sheehan Disability Scale,[37] and Fibromyalgia Health Assessment Questionnaire[37] scores: NS Proportion of patients concurrently using paracetamol and mean total paracetamol dose:[38] NS a p 0.05 for all significant between-group differences. HASD = Hospital Anxiety and Depression Scale; NS = not significant.
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1051 pts assigned to open-label treatment for 6 wk
633 pts (63%) completed
97 pts did not respond
566 pts responded
388 pts (37%) discontinued 78 pts because of lack of efficacy 92 pts defaulted (withdrew consent or were lost to follow-up) 196 pts due to adverse events (178 for treatment-related and 18 for non-treatmentrelated adverse events) 22 pts for other reasons
Enrolled in 26-wk double-blind phase
287 pts randomized to placebo
279 pts randomized to their optimized openlabel dosage of PRE 300, 450 or 600 mg/d
232 pts (81%) discontinued 171 pts due to loss of therapeutic response (34 had <30% improvement in mean pain VAS and 137 had worsening fibromyalgia) 61 pts were censored (34 defaulted; 20 withdrew due to adverse events; 7 for other reasons)
172 pts (62%) discontinued 84 pts due to loss of therapeutic response (14 had <30% improvement in mean pain VAS; 70 had worsening fibromyalgia) 88 pts were censored (31 defaulted; 47 withdrew due to adverse events; 10 for other reasons)
Fig. 3. Simplified diagram of patient (pt) disposition in the FREEDOM trial. Pts with fibromyalgia who responded (defined as a 50% reduction from baseline in pain visual analogue scale [VAS] score plus a rating of overall improvement on the Patient Global Impression of Change scale of much or very much improved) to treatment with oral pregabalin (PRE) in a 6-wk open-label phase were randomized to receive their optimized dosage of PRE 300, 450 or 600 mg/d or placebo in a 26-wk double-blind phase.[40]
or had no post-baseline observations were considered to not have experienced a loss of therapeutic response at their last observation (i.e. were censored). The validity of various censoring assumptions in the primary analysis was tested in sensitivity analyses. The patient disposition in the trial is shown in figure 3. Baseline patient characteristics and demographics were not significantly different between the open-label and double-blind phases.[40] The mean pain VAS score was 78.0 mm prior to the open-label phase and 14.116.0 at the beginning of the double-blind phase.[40]
3.2.1 Time to Loss of Therapeutic Response
The beneficial effects of pregabalin were durable in patients with fibromyalgia who had shown an initial response to open-label pregabalin.[40] The
time to loss of therapeutic response was significantly longer in the pregabalin 300600 mg/day group than in the placebo group (p < 0.001). Based on Kaplan-Meier estimates of time to event, 25% of pregabalin recipients had a loss of therapeutic response by day 34 (95% CI 21, 48), whereas 25% of placebo recipients had a loss of therapeutic response by day 7 (95% CI 5, 9). A loss of therapeutic response in 50% of placebo recipients was shown by day 19 (95% CI 14, 36) but, by the end of the trial, <50% of pregabalin recipients had a loss of therapeutic response. At the end of the 26-week phase, a loss of therapeutic response was experienced by 32% of patients receiving pregabalin and 61% of those receiving placebo.[40] In a dosage group comparison, the time to loss of therapeutic response was significantly (p 0.001)
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longer in the pregabalin 300, 450 and 600 mg/day groups than in the matching placebo groups.[40] The time to loss of therapeutic response in the first quartile with pregabalin 300, 450 and 600 mg/day relative to matched placebo was 122 versus 4 days, 25 versus 7 days and 26 versus 7 days, respectively; the corresponding proportions of patients with loss of therapeutic response by the end of the doubleblind phase were 14% versus 42%, 28% versus 50% and 48% versus 82%.[40] The results of the sensitivity analyses, which tested the validity of the primary assumptions, confirmed the superiority of pregabalin over placebo.[40] The Kaplan-Meier estimates of time to loss of therapeutic response in pregabalin recipients were significantly (p < 0.0001) longer than those in placebo recipients in six prespecified sensitivity analyses that considered the following alternate scenarios: all patients who withdrew early had a loss of therapeutic response; all patients who withdrew early maintained pain relief as long as anyone else in the trial; all patients who withdrew because of an adverse event had a loss of therapeutic response, rather than being censored; all patients who had a <30% reduction in pain VAS scores had a loss of therapeutic response at the first such visit, without the need for confirmation at the next visit; all patients who withdrew before day 8 were censored; and all patients who withdrew because of worsening fibromyalgia were censored, unless confirmed by a <30% reduction in pain VAS score. The robustness of the results of the primary analysis were also shown in two additional post hoc analyses, which were performed to account for possible unblinding as the patients moved from openlabel to double-blind treatment. The time to loss of therapeutic response was significantly (p 0.02) longer in pregabalin than placebo recipients when censoring included either all patients who withdrew before day 15, or all patients with dizziness or somnolence that did not resolve prior to doubleblind treatment.[40] Similarly, pregabalin was favoured over placebo when secondary efficacy endpoints were considered.[40] Kaplan-Meier estimates of the time to loss
of response were significantly (p < 0.001) longer in pregabalin than placebo recipients as assessed by worsening from baseline in the PGIC responses and FIQ, MOS-Sleep overall sleep problems index, MAF, and Short-Form 36 Health Survey (SF-36) physical and mental components scores. Ratings of much or very much improved on the PGIC were no longer reported by 50% of placebo recipients by day 20, whereas a similar loss of response was reported by 50% of pregabalin recipients by day 126 (p < 0.0001).[40] Patients receiving pregabalin had median times to loss of response that were significantly (p < 0.0001) longer than those in placebo recipients as assessed by FIQ total (day 19 vs day 14), MOS-Sleep overall sleep problems index (day 42 vs day 14), MAF (day 119 vs day 27), SF-36 physical component (day 49 vs 15) and SF-36 mental component (day 42 vs day 14) scores. The amount of paracetamol used as a rescue medication did not differ significantly between pregabalin and placebo recipients (165 vs 243 mg/day).[40] 4. Tolerability The tolerability of oral pregabalin 150600 mg/ day in patients with fibromyalgia was evaluated in the clinical trials discussed in section 3.[36-41] This section focuses primarily on the tolerability of pregabalin based on pooled data from the three shortterm clinical trials in patients with fibromyalgia[36-38] (provided in the manufacturers prescribing information[15]) and data from the FREEDOM trial.[40] The adverse events reported in patients with fibromyalgia receiving short-term or continued treatment with pregabalin[36-41] were consistent with the known adverse effects of pregabalin.[15] The most common adverse events, regardless of causality, that occurred in 5% of patients in the total population receiving pregabalin 150600 mg/ day in the three short-term US trials in patients with fibromyalgia are presented in figure 4. Of these, dizziness, somnolence, weight increase, blurred vision, dry mouth, constipation, peripheral oedema, euphoric mood, increased appetite, attention disturbance and balance disorder occurred at incidences in
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Balance disorder Attention disturbance Increased appetite Sinusitis Euphoric mood Peripheral oedema Fatigue Constipation Blurred vision Dry mouth Weight increase Headache Somnolence Dizziness
0 5 1 5 1 5 4 5 1 6 2 6 4 7 2 7 1 8 2 8 2 11 12 12 4 9 20
PL (n = 505) PRE (n = 1517)
38
10
15
20 25 Percentage of pts
30
35
40
Fig. 4. Tolerability of oral pregabalin (PRE) in patients (pts) with fibromyalgia. Descriptive incidence of pooled adverse events, regardless of causality, that occurred in 5% of pts receiving any dosage of PRE (150, 300, 450 or 600 mg/d)[15] in three randomized, double-blind, placebo (PL)-controlled, multicentre trials with a duration of 8,[36] 13[37] or 14[38] wk conducted in the US.
pregabalin recipients that were at least 2-fold those in placebo recipients. During the double-blind phase of the FREEDOM trial in patients who had an initial response to pregabalin, the most common treatment-emergent adverse events (incidence 5%) in pregabalin and placebo recipients were insomnia (both 6%), sinusitis (5% vs 3%), nausea (both 5%), arthralgia (5% vs 2%) anxiety (5% vs 2%) and influenza (5% vs 1%). Reports of adverse events in the double-blind period of the FREEDOM trial represent new onset or change in intensity of previously reported adverse events as of randomization.[40] Although treatment-emergent adverse events were reported in the majority of patients with fibromyalgia receiving pregabalin 150600 mg/day or placebo (7894% and 7277% in the short-term US trials[36-38]), most events in clinical trials were of mild to moderate intensity[15,36-41] and were often of
limited duration.[36,37,41] The occurrence of adverse events of any type increased with increasing dosage.[36-38] Where reported,[38-41] treatment-emergent serious adverse events were not considered to be related to pregabalin,[38,40] or were limited to one event of chest pain in a patient receiving pregabalin 450 mg/day[39] and two other events (description not provided).[41] The emergence of adverse events was a reason for discontinuation of treatment in some patients in clinical trials of pregabalin in fibromyalgia.[36-41] Adverse events led to discontinuation of treatment in 19% of pregabalin and 10% of placebo recipients in the pooled short-term US trials in fibromyalgia.[15] In the FREEDOM trial, adverse events led to the discontinuation of treatment in 19% of pregabalin recipients in the open-label phase, and 17% of pregabalin and 7% of placebo recipients in the double-blind phase.[40]
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Dizziness and somnolence are the most frequent treatment-emergent adverse events associated with pregabalin.[15] The pooled incidences of these events were numerically higher in pregabalin recipients than in the placebo recipients in the short-term US trials in patients with fibromyalgia (figure 4). During the open-label phase of the FREEDOM trial, dizziness and somnolence were reported in 36% and 22% of pregabalin 300600 mg/day recipients.[40] Dizziness and somnolence are generally reported shortly after the initiation of pregabalin therapy, appear to be more frequent at higher dosages, and may be transient or persistent. In the three pooled short-term US trials in patients with fibromyalgia,[15] dizziness and somnolence led to discontinuation in 6% and 3% of pregabalin recipients compared with <1% of placebo recipients. Peripheral oedema has been reported in patients with fibromyalgia receiving pregabalin.[15] The incidence of this adverse event was numerically higher in pregabalin than placebo recipients in the pooled short-term US trials in patients with fibromyalgia (figure 4).[15] However, across short-term clinical trials in various patient populations without clinically significant heart or peripheral vascular disease, peripheral oedema has not been associated with cardiovascular complications or laboratory changes suggestive of deterioration in renal or hepatic function.[15] Weight gain has also been associated with pregabalin.[15] In the pooled short-term trials in patients with fibromyalgia, 11% of pregabalin and 2% of placebo recipients had a weight gain of 7% of baseline weight (figure 4); increased weight was the reason for discontinuation in 1% of pregabalin recipients. In the FREEDOM trial,[40] weight gain was reported by 11% of pregabalin recipients in the open-label phase and 4% in the double-blind phase. Although pregabalin-related weight gain was not associated with clinically important changes in glycaemic control in diabetic patients or blood pressure across short-term clinical trials in various patient populations, the long-term effects of pregabalinrelated weight gain on cardiovascular effects or glycaemic control are not currently known.[15]
Pregabalin has been associated with vision-related events, primarily blurred vision.[15] The incidence of blurred vision was numerically higher in pregabalin recipients than in placebo recipients in the pooled results of the short-term US trials in patients with fibromyalgia (figure 4). Blurred vision resolves with continued pregabalin treatment in the majority of patients and the clinical significance of visionrelated effects is not currently known.[15] No clinically significant findings on laboratory evaluations,[36-38,40,41] ECGs,[36-38] or physical[36-38,40] or neurological[36,38,40] examinations were reported in clinical trials of pregabalin in patients with fibromyalgia. However, across all clinical trials in various patient populations, elevated creatine kinase levels, decreased platelet counts and prolonged PR intervals have been associated with pregabalin.[15] Treatment with pregabalin has also been associated with angioedema and hypersensitivity in various patient populations in post-marketing reports.[15] Pregabalin should be discontinued immediately in patients reporting these symptoms. The tumourigenic potential of pregabalin has not been established.[15] Although studies in two different strains of mice have shown an unexpectedly high incidence of malignant vascular tumours, the clinical significant of this finding is not known.[15] New or worsening tumours were reported in 57 patients in clinical studies with 6396 patient-years of pregabalin exposure in various patient populations, but the effect of pregabalin treatment on tumours is not possible without knowledge of the background incidence and recurrence in similar populations who did not receive pregabalin treatment.[15] 5. Dosage and Administration Oral pregabalin is indicated in the management of adults with fibromyalgia in the US[15] and several other countries. In this patient population, the recommended dosage of pregabalin is 300450 mg/ day administered in two divided doses per day (with or without food). The initial dosage of pregabalin 150 mg/day may be increased to 300 mg/day within 1 week (based on individual patient response and tolerability) and may be further increased to 450 mg/
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day if required.[15] If discontinuation of pregabalin is necessary, the dosage of the drug should be tapered gradually over a period of at least 1 week.[15] Dosage reductions of pregabalin are necessary in patients with impaired renal function, as clearance of the drug is directly related to CLCR (section 2.3).[15] Reductions should be based on the patients CLCR, with the pregabalin dosage reduced by 50% for each 50% decrease in CLCR.[15] In addition, as haemodialysis removes pregabalin from the circulation (section 2.3), patients undergoing haemodialysis should receive a single supplemental pregabalin dose immediately following each 4-hour haemodialysis treatment.[15] Local prescribing information should be consulted for further details regarding contraindications, warnings, precautions and use in special populations. 6. Place of Pregabalin in the Management of Fibromyalgia Fibromyalgia is characterized by chronic and widespread muscle pain and tenderness, which are used to distinguish fibromyalgia from other rheumatic disorders.[1,4,5,10] The pain, disordered sleep and fatigue associated with fibromyalgia have a negative effect on daily life, and are associated with impaired physical functioning, overall health status and capacity to work.[4,46] Family problems, feelings of hopelessness and isolation may result from the patients diminished capacity to participate in daily life and social activities, and economic problems may result from the inability of the patient to continue to work.[47] The goals of treatment of fibromyalgia are to alleviate pain, increase restorative sleep and improve physical function.[11,48] As fibromyalgia is a complex and difficult-to-treat disorder, a multidisciplinary approach is suggested by treatment guidelines.[1-3] Nonpharmacological therapies (e.g. exercise, cognitive behavioural therapy and patient education) appear to be helpful in reducing pain and treating other symptoms.[1-3] Recommendations for empirical pharmacological therapy have been based on drugs (e.g. tricyclic antidepressants, selective
serotonin reuptake inhibitors, analgesics, muscle relaxants and hypnotics) that have neuromodulatory activity.[1-4] Such agents have been used to manage single symptoms, rather than the condition, as none of these single agents has shown consistent efficacy across all symptom domains.[48] Available guidelines[1-3] were published prior to the recent FDA approvals of pregabalin and duloxetine as first-line treatments for fibromyalgia. Pregabalin was the first agent to be approved by the FDA for the treatment of fibromyalgia.[13] In contrast to empirical therapies, monotherapy with pregabalin (section 3) has shown a multidimensional effect in the treatment of fibromyalgia.[48] Its analgesic and anxiolytic activity in animal models appears to be related to its capacity to selectively bind to the 2 subunit of voltage-gated calcium channels in the CNS, thereby reducing the release of several neurotransmitters (section 2). The reduction in neurotransmitter release from neurons in the spinal cord and brain may be the mechanism of action responsible for the clinical benefits of pregabalin in trials in patients with fibromyalgia. Monotherapy with pregabalin is effective in rapidly relieving pain in patients with long-standing fibromyalgia and moderate to severe levels of pain (section 3). The proportion of patients with a clinically significant decrease in pain (i.e. a 30% decrease in mean pain NRS score) was significantly higher with pregabalin 300, 450 or 600 mg/day than with placebo in some, but not all, treatment groups in short-term trials (section 3.1). Pregabalin is also associated with improvements in several sleep parameters and overall health status (section 3.1). The efficacy of pregabalin is durable in patients who initially respond to treatment with the drug. The time to loss of therapeutic response was significantly longer in patients receiving pregabalin 300600 mg/day than in those receiving placebo based on a number of efficacy and sensitivity analyses in the FREEDOM trial (section 3.2). Although a relatively large proportion of patients did not respond to pregabalin therapy in this trial, patients had severe pain at baseline and, therefore, may not have been able to achieve the demanding predefined criDrugs 2008; 68 (15)
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teria for response (50% reduction in pain VAS score plus an overall impression of much or very much improved health). However, according to an editorial,[49] interpretation of the results of long-term trials of pregabalin and other agents in the management of fibromyalgia may be quite difficult due to placebo effects linked to the study design. The enrichment design of the FREEDOM trial (i.e. pregabalin responders in the open-label phase were enrolled in the double-blind phase) may have compromised the blinding in the pregabalin and placebo groups, as well as inflating the between-group difference in pain levels.[49] Of note, the results of the primary analysis were robust in two post hoc analyses (section 3.2) performed to account for possible unblinding as the patients moved from open-label to double-blind treatment. Fibromyalgia, in common with other chronic pain conditions, has been strongly associated with symptoms of anxiety and depression, which may have a potential effect on the response to treatment.[50] However, pregabalin appears to be effective in reducing pain regardless of whether patients have co-morbid anxiety or depressive symptoms. In a pooled analysis of the three short-term US trials,[42] although over one-third of patients had moderate to severe anxiety and over one-quarter had moderate to severe depression, there did not appear to be a significant association between baseline levels of anxiety and depression and the efficacy of pregabalin in reducing pain (section 3.1.1). Of note, these trials may underestimate the rates of anxiety and depressive symptoms in patients with fibromyalgia, as the trials excluded patients with clinically significant or unstable psychiatric conditions, or who were unable to withdraw from psychotropic medications. Adverse events are common with pregabalin, but are generally of mild to moderate intensity (section 4). Many patients tolerate the adverse events and continue with pregabalin treatment; however, adverse events led to discontinuation of pregabalin in approximately one-fifth of patients in clinical trials. In the pooled results of the three short-term US trials, for example, dizziness and somnolence, the
most commonly reported adverse events, were reported in 38% and 20% of pregabalin recipients, but only led to discontinuation of treatment in 6% and 3% of pregabalin recipients. The recommended titration of pregabalin based on response and tolerability (section 5) may help reduce the incidence of adverse events. As the adverse events associated with pregabalin are dose-related and treatment with dosages of 600 mg/day did not appear to confer additional benefit in clinical trials, treatment with pregabalin at dosages >450 mg/day is not recommended.[15] The pharmacokinetic profile of pregabalin (section 2.3) is favourable. Unlike the dose-limited absorption of gabapentin, absorption of pregabalin is not saturable, resulting in a linear pharmacokinetic profile.[20] Pregabalin has a rapid onset of action, as shown by the observed onset of efficacy as early as week 1 in clinical trials (section 3.1). Dosage titration of pregabalin is based on individual patient response and tolerability (section 5). The dosage regimen of pregabalin (twice daily with or without food) is convenient and uncomplicated, which may aid compliance. The agent is not associated with clinically relevant drug interactions (section 2.3), which is beneficial in patients who may be receiving a number of different medications. The selective serotonin and norepinephrine reuptake inhibitor duloxetine has also been recently approved by the FDA for the treatment of fibromyalgia,[14] and has shown efficacy in the treatment of this condition in clinical trials.[51,52] Both pregabalin and duloxetine have been effective in treating the symptoms of fibromyalgia in only a certain proportion of patients. Given the complex nature of the condition and the number of patients who are refractory to treatment with the agents, well designed clinical trials comparing the efficacy of pregabalin with that of duloxetine may be beneficial in identifying subgroups of patients with potentially differing pathophysiology who would benefit from treatment with one agent over the other. Evaluations of the effectiveness of monotherapy or combination therapy with pregabalin versus other pharmacological and nonpharmacological therapies would also be of
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value. Although further study is required, an openlabel prospective trial in 19 patients with fibromyalgia suggested that pregabalin may be a useful augmentation strategy in patients who partially respond to treatment with quetiapine.[53] Although the direct medical costs (e.g. costs of visits to healthcare providers and pharmacological and nonpharmacological treatment) associated with chronic pain conditions, such as fibromyalgia, can be high, a substantial burden is also placed on individuals and society by the indirect costs of absenteeism and lost productivity.[46] Effective treatment of the core symptoms of fibromyalgia may allow patients to return to the workforce or increase their productivity, thereby reducing loss-of-productivity costs. Pharmacoeconomic analyses from a societal perspective based on long-term clinical data are required to provide information on the potential cost effectiveness of pregabalin relative to other pharmacological and nonpharmacological therapies in the treatment of fibromyalgia. In conclusion, oral pregabalin has a multidimensional effect in the treatment of fibromyalgia. It is associated with rapid and clinically significant improvements in several outcome measures relating to core symptoms of this complex syndrome, including pain and sleep, in patients with long-standing fibromyalgia. Pregabalin is also associated with improvements in overall health status. The beneficial effects of pregabalin are durable in patients with an initial response to the drug. The most common adverse events associated with the drug are dizziness and somnolence, which are generally mild to moderate in intensity and are tolerated by many patients. Pregabalin is, therefore, a valuable option in the first-line treatment of patients with fibromyalgia. Disclosure
The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.
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Correspondence: Katherine A. Lyseng-Williamson, Wolters Kluwer Health | Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand. E-mail: demail@adis.co.nz
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ADIS DRUG EVALUATION

Lyseng-Williamson & Siddiqui

2008 Adis Data Information BV. All rights reserved.

Lyseng-Williamson & Siddiqui

(S) H2N HO2C

Fig. 1. Chemical structure of pregabalin

2008 Adis Data Information BV. All rights reserved.

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Lyseng-Williamson & Siddiqui

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NRS = numerical rating scale.

3.1 Short-Term Fixed-Dosage Trials

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Mean pain numerical rating scale score (primary[36] or co-primary[37,38] endpoint)a,b

No. of pts evaluated

Change from baseline

Treatment difference (PRE vs PL)

2008 Adis Data Information BV. All rights reserved.

Percentage of pts with 30% decrease in score

Percentage of pts with 50% decrease in score

No. of pts evaluated

Change from baseline

Treatment difference (PRE vs PL)

No. of pts evaluated

Change from baseline

Treatment difference (PRE vs PL)

No. of pts evaluated

Change from baseline

Treatment difference (PRE vs PL)

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Lyseng-Williamson & Siddiqui

Any worsening No change Any improvement

17% 12% 71% 72%

18% 10% 69%

23% 20% 56% 21%

PRE 300 (n = 175) b

PRE 450 (n = 173)

PRE 600 (n = 175)

18% 14% 68% 77%

18% 16% 66% 47%

PRE 300 (n = 183)

PRE 450 (n =190)

PRE 600 (n = 188)

treatment regardless of whether patients had baseline anxiety or depressive symptoms.[43]

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Lyseng-Williamson & Siddiqui

1051 pts assigned to open-label treatment for 6 wk

633 pts (63%) completed

97 pts did not respond

566 pts responded

Enrolled in 26-wk double-blind phase

287 pts randomized to placebo

55 pts (19%) completed

107 pts (38%) completed

Lyseng-Williamson & Siddiqui

PL (n = 505) PRE (n = 1517)

Lyseng-Williamson & Siddiqui

Lyseng-Williamson & Siddiqui

2008 Adis Data Information BV. All rights reserved.

Drugs 2008; 68 (15)

24. 25. 26.

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Drugs 2008; 68 (15)