Fibromialgia y Pregabalina

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Drugs 2008; 68 (15): 2205-2223ADIS DRUG EVALUATION 0012-6667/08/0015-2205/$53.45/0

2008 Adis Data Information BV. All rights reserved.

PregabalinA Review of its Use in Fibromyalgia

Katherine A. Lyseng-Williamson andM. Asif A. Siddiqui

Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters KluwerHealth, 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, TrinityHealth Center, Minot, North Dakota, USA;K.. Forseth, Department of Rheumatology, National Hospital,Oslo, Norway; M.J. Puszczewicz, Department of Rheumatology, Rehabilitation and Internal Medicine,University of Medical Sciences, Poznan, Poland.

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 Bibliographical information, including contributory unpublished data, was also requested from the company developing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 ofthe 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22061. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2207

2. Pharmacological Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22082.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22082.2 Other Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22082.3 Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22092.4 Potential Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2210

3. Therapeutic Efficacy in Fibromyalgia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22103.1 Short-Term Fixed-Dosage Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2211

3.1.1 Primary Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22113.1.2 Secondary Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2214

3.2 Durability-of-Response (FREEDOM) Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22153.2.1 Time to Loss of Therapeutic Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2216

4. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2217

5. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22196. Place of Pregabalin in the Management of Fibromyalgia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2220


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2206 Lyseng-Williamson & Siddiqui

SummaryOral pregabalin, a calcium channel 2-subunit ligand with analgesic, anxiolyticAbstractand 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-gatedPharmacologicalcalcium channels, which are widely distributed throughout the central and peri-Propertiespheral 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-morbidi-

ties 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 arerequired in patients with impaired renal function.

Oral pregabalin was generally associated with improvements from baseline inTherapeutic Efficacymean 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 generallysustained 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 (addition-

al 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 end-

point), 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 withimprovements in several sleep parameters in the short-term trials. Significant

2008 Adis Data Information BV. All rights reserved. Drugs 2008; 68 (15)


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Pregabalin: A Review 2207

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 res-

ponse 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.

The tolerability profile of pregabalin in patients with fibromyalgia is consistentTolerabilitywith the known adverse effects the drug. Although adverse events were frequently

reported in the pregabalin and placebo groups in clinical trials in patients withfibromyalgia, most events were of mild to moderate intensity and were often of

limited duration.

The treatment-emergent adverse events most frequently associated with pre-

gabalin 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 discontinua-

tion of pregabalin therapy in only some patients.

1. Introduction (e.g. irritable bowel and bladder syndromes),temporomandibular joint syndrome, restless legs

Fibromyalgia is a complex, idiopathic non- syndrome and psychological disturbances (e.g. de-

progressive clinical pain syndrome[1-5] that affects pression, anxiety, and memory and cognitive prob-

24% of the general population in the US and is lems.).[1,4,6,9,10] Inflammation is not associated with

predominantly seen in women.[5] The onset of symp- fibromyalgia.[5] The pain and other symptoms oftoms typically occurs at 2050 years of age, but may fibromyalgia vary in intensity, and relapse and remit

present at any age.[4] over time.[4,10]

Because of the lack of objective diagnostic mark- Although the aetiopathological processes of

ers, muscle pain and tenderness (the defining char- fibromyalgia are unclear and no widely accepted

acteristics of fibromyalgia) are used to distinguish model of the disorder currently exists, the syndromethe condition from other rheumatic disorders.[5] Al- appears likely to be a dysfunction of pain-modulato-

though their use as a diagnostic tool in clinical ry systems within the CNS.[9,11] Neurobiological

practice has been the subject of some debate,[6,7] the studies indicate that fibromyalgia-related pain may

1990 American College of Rheumatology (ACR) involve augmented central pain processing, result-

classification criteria,[8] which were intended to ing in patients experiencing pain without appropri-

standardize research studies, define fibromyalgia as ate peripheral nociceptive input.[6,9,11] Pain and other

widespread aching pain for at least 3 months and features of fibromyalgia may involve dysfunction of

hyperalgesia at a minimum of 11 of the 18 specified the autonomic nervous system and the hypothala-

muscle-tendon sites. Among the possible accom- mic-pituitary adrenal axis.[10,11] Genetic, environ-

panying symptoms are fatigue, sleep disturbances, mental (e.g. co-morbid disease, infections or physi-

headache, morning stiffness, subjective swollen cal trauma) and psychological (e.g. somatization,joint feeling, paraesthesia, autonomic symptoms anxiety, and personal or family history of depres-



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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

H2N(S)

HO2CFig. 1. Chemical structure of pregabalin

(e.g. exercise, cognitive behavioural therapy and

patient education) are recommended to help reduce site as gabapentin; the two agents have similar, butpain and treat other symptoms.[1-3] In the past, drug not identical, pharmacological profiles.[11,18-20]therapy was mostly based on empirical research; In vitro, pregabalin selectively binds with highhowever, the US FDA has approved two oral agents affinity to the 2 subunit of voltage-gated calciumfor the treatment of fibromyalgia. channels, which are widely distributed throughout

The first agent to be approved was pregabalin the central and peripheral nervous systems.[20] The(Lyrica 1),[13] which has been followed by the more subsequent attenuation of Ca2+ ion influx at pre-recent approval of duloxetine.[14] This article pro- synaptic nerve endings appears to modulate the ex-vides a review of the pharmacology, therapeutic cessive release of several excitatory neurotransmit-efficacy and tolerability of oral pregabalin in pa- ters, including glutamate, norepinephrine (norad-tients with fibromyalgia. A discussion of the use of renaline), substance P and calcitonin gene-relatedpregabalin in other indications approved in the peptide.[22,23] A study in mice with a mutation of theUS[15] or EU[16] (adjunctive therapy for partial onset 2-1 subunit protein of voltage-gated calciumseizures [US[15] and EU[16]], neuropathic pain asso- channels confirmed that the analgesic effects ofciated with diabetic peripheral neuropathy [US],[15] pregabalin are mediated through binding to thepostherpetic neuralgia [US],[15] generalized anxiety 2-1 subunit.[26]disorder [EU],[16] and peripheral and central neuro- Although pregabalin is a structural derivative ofpathic pain [EU][16]) is beyond the scope of this the inhibitory neurotransmitter GABA, it does not

article. interact with GABAA, GABAB or benzodiazepinereceptors, alter rat brain GABA levels or augment

2. Pharmacological PropertiesGABAA responses in cultured neurons.[15,19,21]

While pregabalin does not acutely inhibit GABAPregabalin is associated with analgesic, anxiolyt-reuptake, with prolonged exposure to cultured neu-ic and antiepileptic activity.[17-25] This section pro-rons, it produces a paradoxical enhancement ofvides a summary of the pharmacological propertiesGABA uptake by increasing the redistribution ofof pregabalin that may be important to its efficacy inGABA-transporter protein to the cell surface.[15]the treatment of fibromyalgia based on data fromPregabalin does not block sodium channels, inhibitprevious reviews,[17-25] studies in animals,[26-29]

dopamine, serotonin or norepinephrine reuptake,healthy volunteers[30,31] or patients,[32] the manufac-

have activity at opioid, serotonin or dopamine re-turers prescribing information[15] and pharmacokin-ceptors, or alter cycloxygenase enzyme activity.[15]etic studies.[33-35] Some studies are available as ab-

stracts.[27,33,34] The effect of pregabalin on pain,2.2 Other Pharmacodynamic Propertiessleep and other parameters in patients with fibromy-

algia is discussed in section 3.Pregabalin demonstrated beneficial effects on the

key symptoms and co-morbidities associated with2.1 Mechanism of Action

fibromyalgia (i.e. pain, anxiety and sleep) in animalPregabalin is the pharmacologically active S- models.[17,18,26-29] Pregabalin dose-dependently in-

etantiomer of 3-aminomethyl-5-methyl-hexanoic hibited capsaicin-induced allodynia,[27] produced

acid (figure 1).[15] It interacts with the same binding anxiolytic-like effects[28] and increased slow-wave

1 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 dem- (75900 mg/day) is dose proportional.[15] After a

onstrated antiallodynic and antihyperalgesic activi- single dose of pregabalin 300 mg, mean values for

ties in a number of other rodent models of pain peak plasma concentration and area under the plas-

(including mechanical allodynia induced by vincris- ma concentration-time curve were 9.46 g/mL andtine, streptozocin, nerve injury or surgery, and hy- 66.3 g h/mL.[33] Steady-state concentrations areperalgesia induced by formalin, carrageenan, sub- reached within 2448 hours following administra-stance P, NMDA and thermal injury).[17] The antial- tion of multiple doses of pregabalin.[15]

lodynic and antihyperalgesic effects of pregabalin The oral bioavailability of pregabalin is highwere observed at dosages that were one-quarter to (90%) and independent of dose.[15] Although ad-one-half of those of gabapentin.[18] ministering pregabalin with food delays the rate of

Pregabalin did not generally impair cognitive and absorption of the drug, it does not affect the extentpsychomotor function[30] and modestly improved of its absorption.[15]

some measures of sleep architecture and sleep[31] in Pregabalin is not bound to plasma proteins anda randomized, double-blind, placebo-controlled has an apparent volume of distribution of0.5 L/crossover study in 24 healthy volunteers. In assess- kg.[15] Pregabalin, which is a substrate of the systemments of cognitive and psychomotor function using L transporter that transports large amino acidsa validated test battery, pregabalin 450 mg/day did across the brain and gut, crossed the blood-brainnot significantly impair reaction time, vigilance or barrier in preclinical animal studies;[15,25] however,serial memory scanning relative to placebo, but was studies of such transport in humans are currentlyassociated with transient minor impairment of CNS lacking.[15]arousal, divided attention and sedation (all p < 0.05),

Metabolism of pregabalin is negligible, withand modestly improved brake reaction time

most of the drug being excreted unchanged in the(p < 0.05).[30]

urine.[15,34] In healthy volunteers, 90% of a radio-Relative to placebo, pregabalin 450 mg/day was labelled 100 mg dose of pregabalin was excreted in

associated with small, but significant (p < 0.05),the urine as unchanged drug and only 0.9% was

improvements in slow-wave (stage 3/4) sleep andaccounted for by the major metabolite of pregabalin

time to sleep-onset latency, but a significantly lower(theN-methylated derivative).[34] Less than 0.1% of

proportion of rapid-eye-movement sleep during thethe dose was recovered in the faeces.[34] In healthy

total sleep period in the crossover study.[31] More-volunteers with normal renal function, the mean

over, in an exploratory 4-week, randomized, double-elimination half-life (t1/2) was 6.3 hours and wasblind study in 15 epileptic patients with clinicallyindependent of dose.[15]

relevant sleep disturbance, pregabalin was asso-Mean values for renal clearance of pregabalin inciated with improvements in sleep continuity rela-

young healthy volunteers (67.080.9 mL/min), to-

tive to placebo that appeared to be independent of gether with the lack of plasma protein binding of theseizure control.[32]drug, indicate that renal tubular reabsorption is in-volved in pregabalin clearance.[15]2.3 Pharmacokinetic Properties

Clearance of pregabalin is directly related to cre-The pharmacokinetics of pregabalin in patients atinine clearance (CLCR).[35] In a study in 38 patients

with fibromyalgia have not been investigated; there- with various degrees of renal impairment (includingfore, data in healthy volunteers administered single 12 undergoing haemodialysis),[35] exposure to pre-or repeated doses of pregabalin are reported, unless gabalin increased with decreasing renal function andotherwise indicated. pregabalin was highly cleared by haemodialysis.

Oral pregabalin is absorbed rapidly (peak plasma Dosage adjustments are, therefore, necessary in pa-

concentrations occur within 1.5 hours), and expo- tients with impaired renal function or those undergo-sure to single (25300 mg/day) or multiple dosages ing haemodialysis (section 5).[15] Clearance of pre-



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gabalin is not affected by sex or race, but is de- South America; n = 735),[39] pooled analyses of the

creased in the elderly, which is consistent with age- three short-term US trials,[42,43] and a 1-year open-related changes in renal function.[15] label extension study of the 13-week trial[41] are also

briefly discussed. The total daily dose of oral pre-

gabalin (administered as two divided doses in most2.4 Potential Drug Interactions

trials[37-40] and three divided doses in one trial[36]) isPregabalin has not been, and is unlikely to be, reported.

associated with any pharmacokinetic drug interac-For inclusion in the placebo-controlled

tions.[15,20,24,25] As pregabalin does not undergo hep-trials,[36-40] patients aged 18 years were required to

atic metabolism and does not induce or inhibit cyto-meet the 1990 ACR criteria for fibromyalgia (i.e.

chrome P450 (CYP) enzyme systems in vitro, it iswidespread pain for 3 months and pain in 11 of 18

not anticipated that it will interact with CYP1A2 andspecific tender points) and have a baseline pain

CYP3A4 substrates.[15] In pharmacokinetic analyses

visual analogue scale (VAS) score 40 mm on ain healthy volunteers and various patient popula- scale of 0100 mm. In the 8- to 14-week trials,[36-38]tions, the pharmacokinetics of pregabalin were notpatients were also required to have mean daily diarysignificantly affected by concomitant administrationpain numerical rating scale (NRS) scores 4 on aof lorazepam, oxycodone, alcohol, antihypergly-scale of 010 during the week before randomiza-caemics (glibenclamide [glyburide], insulin andtion.[36-39]metformin), furosemide (frusemide) and numerous

anticonvulsants.[15] Pregabalin did not have any ef- Among exclusion criteria were evidence of in-

fect on the pharmacokinetics of an oral contracep- flammatory or rheumatological disease, other severetive (norethisterone [norethindrone]/ethinylestradiol painful disorders, clinically significant or unstable1 g/35 g), lorazepam, oxycodone, alcohol and medical or psychiatric disorders, and a calculated

numerous anticonvulsants.[15]

CLCR 60 mL/min.[36-40] The 8-week trial excludedConcomitant administration of pregabalin with patients in whom fibromyalgia-related pain had not

oxycodone, lorazepam or alcohol (ethanol) had an responded to treatment with gabapentin 1.2 g/additive pharmacodynamic effect on cognitive and day.[36] Patients could not receive other medicationsgross motor functioning, but not on respiration.[15] for the treatment of fibromyalgia or its associated

co-morbidities (e.g. antidepressants, anticonvul-3. Therapeutic Efficacy in Fibromyalgia sants, most analgesics, hypnotics, sedatives or other

agents),[36-40] but, where stated, were permitted toThe therapeutic efficacy of pregabalin monother- receive 4 g/day of paracetamol (acetaminophen) as

apy in the treatment of adults with fibromyalgia has rescue medication for pain,[36-38,40] 325 mg/day ofbeen evaluated in several randomized, double-blind,

aspirin (acetylsalicylic acid) for cardiac prophylax-placebo-controlled, multicentre trials.[36-40] This sec- is[36-38] and stable nonpharmacological therapy.[36-38]tion focuses on the results of fully published trials

Baseline patient characteristics and demograph-conducted in the US, including three short-term

ics were not significantly different between random-(duration of 8,[36] 13[37] or 14[38] weeks) trials

ized treatment groups in any of the trials.[36-40](n = 529748; section 3.1), and the longer durabili-Across treatment arms in all trials,[36-40] the meanty-of-response FREEDOM (Fibromyalgia relapseduration of fibromyalgia was 711 years, the meanevaluation and efficacy for durability of meaningfulpatient age was 4851 years and the majorityrelief) trial (n = 566; section 3.2).[40] Preliminary(9196%) of patients were women. In the US trials,results (i.e. currently available as an abstract[41] ormost (8895%) of the patients in each treatment armabstracts plus posters[39,42,43]) of an international

were White,[36-40]

whereas 75% of patients were14-week trial conducted in countries other than theWhite in the international trial.[39]US (Europe, Asia, Australia, Canada, Mexico and



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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 Description/comments

Primary or co-primary endpointsPain NRS scorea 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]

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 Pt-rated instrument that measures changes in overall health status on a scale of 1 (very much improved) to

Changeb,c 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 Assesses sleep quality on an 11-point scale (010)

Rating of sleep quality reported in pt diary each day

Medical Outcome Study- Assesses multiple aspects of pts sleep profile and overall sleep problems on seven subscales (sleep

Sleep scale scores 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

a 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).

b Additional co-primary endpoint that was used only if a significant between-group difference in mean pain NRS score was

achieved.[37,38]

c Co-primary endpoint.[39]

NRS = numerical rating scale.

3.1 Short-Term Fixed-Dosage Trials were assessed in each trial (see table I for a descrip-tion of selected key endpoints).[36-39]

The 8-week trial evaluated the efficacy of pre- Analyses were performed on the intent-to-treatgabalin 150, 300 or 450 mg/day versus placebo; (ITT) population (defined as all randomized patientspatients randomized to the 450 mg/day dosage re- who received at least one dose of study med-ceived 300 mg/day for the first 3 days, followed by ication, using the last-observation-carried-forward450 mg/day thereafter.[36] In the 13-[37] or 14- method.[36-39] Where applicable, endpoints wereweek[38,39] trials, patients were randomized to treat- analysed using ANCOVA models and adjustmentment with pregabalin 300, 450 or 600 mg/day or for multiple comparisons was made based onplacebo; a 1-week single-blinded, placebo run-in Hochbergs procedures.[36-39] Patient Global Impres-phase was followed by a 1-[37] or 2-week[38,39] dou- sion of Change (PGIC) responses and proportionsble-blind, dosage-escalation period and then by of responders were analysed using the Cochran-12 weeks of double-blind fixed-dosage treatment. Mantel-Haenszel procedure, with adjustment forAll trials had a 1-week follow-up phase.[36-39] In the centre.[36-39]

14-week studies, patients who responded to placebo(i.e. those with 30% decrease in pain VAS) in the 3.1.1 Primary Endpointsinitial 1-week run-in phase were not randomized Pregabalin treatment was generally associatedinto subsequent phases of the trials.[38,39] At base- with improvements (i.e. decrease) from baseline inline, mean pain NRS scores across treatment arms mean pain scores.[36-39] In the US trials, relative towere 6.67.3.[36-39] patients receiving placebo, recipients of pregabalin

A number of primary and secondary efficacy 450 or 600 mg/day demonstrated significant im-endpoints related to the symptoms of fibromyalgia provements from baseline in endpoint mean pain



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NRS scores,[36-38] with recipients of pregabalin icant for the pregabalin 450 mg/day arm (between-

300 mg/day also showing significant improvements group difference 5.87; p = 0.001), but not for thein two of the trials[37,38] (table II). In preliminary pregabalin 300 and 600 mg/day arms (numericalresults of the international trial, mean changes from data not reported).[39]

baseline in mean pain NRS scores were significantlyPatient-rated overall status, as assessed by PGIC

different between pregabalin 450 mg/day and place-response, generally improved in patients with fibro-

bo recipients (between-group difference 0.54;myalgia receiving pregabalin.[37-39] In both US

p = 0.02), but not between pregabalin 300 ortrials,[37,38] significant (p < 0.05) differences in the

600 mg/day and placebo recipients (between-groupPGIC response favouring pregabalin over placebo

differences 0.34 and 0.23).[39]were shown for the pregabalin 300, 450 or 600 mg/

In all trials, mean pain NRS scores for all pre- day treatment groups (figure 2). In the internationalgabalin arms were significantly different from those trial,[39] significant (p 0.05) between-group differ-for the placebo arms as early as week 1,[36-39] with

ences in the proportion of patients with improvedsignificant improvements generally sustained overall PGIC status (co-primary endpoint) werethrough most or all weeks of the treatment period in shown with pregabalin 450 mg/day (73%) andthe pregabalin 300,[37,38] 450[36-39] and 600[37-39] mg/ 600 mg/day (69%) versus placebo (56%), but notday arms. In a pooled analysis of the endpoint with pregabalin 300 mg/day (67%).results of the three US trials (n = 2013), [42] pre-

The association between either changes in pain orgabalin 300, 450 and 600 mg/day were associatedPGIC response and changes in other endpoints waswith significant (p < 0.001) and clinically relevantconsidered in an exploratory analysis[42] based onimprovements from baseline in mean pain NRSpooled results of the three US trials.[36-38] Changes inscores relative to placebo.mean pain NRS scores were highly correlated with

The proportion of patients who responded tochanges in mean sleep quality NRS scores and mod-treatment (defined as a 30% or 50% decrease inerately correlated with changes in fatigue (as as-

mean pain NRS score) was significantly (p < 0.05)sessed by Multidimensional Assessment of Fatigue

higher in some pregabalin (300,[38] 450[36,38] or[MAF] scores), but showed little correlation with600[38] mg/day) arms than in the placebo arms in twomood, anxiety and/or depressive symptoms (as as-trials,[36,38] but between-group differences were notsessed by Hospital Anxiety and Depression Scalesignificant for any pregabalin dosage in the other[HADS]-Depression [HADS-D] and HADS-Anxie-trial[37] (table II).ty [HADS-A] subscale scores).[42] Pain improve-

As the first co-primary endpoint (significant be- ment had the greatest impact on the likelihood of atween-group difference in mean pain NRS score) patient being a PGIC responder, followed by thewas met in the 13-[37] and 14-week[38] US trials, two

improvement in sleep quality. Fatigue had only anadditional co-primary endpoints (changes fromintermediate impact and the predicted impact of

baseline in Fibromyalgia Impact Questionnairemood, anxiety and/or depressive symptoms ap-

[FIQ] total scores at endpoint and PGIC at thepeared quite modest.[42]

termination visit) were assessed. Improvements inMoreover, a post hoc analysis based on pooledFIQ total scores in the pregabalin 450 and 600 mg/

data[43] from the three US trials[36-38] suggests thatday groups were significantly better than those inpregabalin reduces pain in patients with or withoutthe placebo groups in one trial,[38] but there was nosymptoms of anxiety or depression. Although 38%significant difference between placebo and any ofof patients had moderate to severe anxiety andthe pregabalin groups in the other trial[37] (table II).27% had moderate to severe depression (HADS-AIn the international trial, differences between the

or HADS-D score 11 on scales of 021) at base-pregabalin and placebo arms in the mean improve-line, pain improved significantly with pregabalinment from baseline in FIQ total score were signif-



9/19


10/19


PRE 300 (n = 175)

17%

12%

71%

PRE 450 (n = 173)

18%

10%

72%

PRE 600 (n = 175)

11%

20%

69%

PL (n = 178)

23%

21%56%

a

b

PRE 300 (n = 183)

18%

14%

68%

PRE 450 (n =190)

12%11%

77%

PRE 600 (n = 188)

18%

16%

66%

PL (n = 184)

22%

31%

47%

Any worsening

No change

Any improvement

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 base- from baseline in MOS-Sleep somnolence subscale

line anxiety or depressive symptoms.[43] scores than placebo recipients.[37] Somnolence is a

commonly reported adverse event in clinical trials of3.1.2 Secondary Endpoints

pregabalin (see section 4).Pregabalin was associated with improvements in

Only some of the other secondary endpointssleep.[36-39] In secondary analyses of the effect ofshowed significant differences in changes frompregabalin on sleep in the US trials, patients receiv-baseline in patients receiving pregabalin relative toing pregabalin 300, 450 and 600 mg/day showedthose receiving placebo in the US trials (table III).significant (p < 0.05) improvements in sleep qualityAny significant between-group differences in these(as measured by the decrease from baseline in meanparameters were usually shown in the recipients ofsleep quality NRS scores) relative to patients receiv-the higher pregabalin dosages and were often noting placebo (table II).[36-38] In addition, where re-consistently displayed across trials (table III).ported, pregabalin 300, 450 and 600 mg/day recipi-

ents had significant (p < 0.05) improvements from The efficacy of long-term treatment with pre-

baseline relative to placebo recipients with regard to gabalin has been shown in preliminary results of a 1-

several parameters measured by the Medical Out- year open-label extension[41] of the 13-week double-

comes Study (MOS)-Sleep scale (overall sleep blind US trial in patients with fibromyalgia.[37] Of

problems index [table II],[36-38] sleep distur- the 429 patients who entered the study, 249 (58%)

bance,[37,39] sleep adequacy [300 and 450 mg/day completed the study (median duration of pregabalin

only],[37] sleep quantity[37] and sleep quality[38]). treatment 357 days).[41] Pregabalin 150600 mg/day

However, recipients of pregabalin 450 and 600 mg/ was associated with improvements from baseline inday had significantly (p < 0.05) greater increases pain as assessed by Short-Form McGill Pain Ques-



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tionnaire pain VAS scores and total pain, sensory at both of two timepoints (week 4 or 5 and week 6)

pain, affective pain and present pain intensity do- of the open-label phase.[40]

main scores.[41]

The primary efficacy endpoint was the differencebetween all pregabalin and all placebo recipients in

3.2 Durability-of-Response (FREEDOM) Trial the time to loss of therapeutic response (defined as

either a


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97 pts did not

respond

566 pts

responded

55 pts (19%)

completed

107 pts (38%)

completed

232 pts (81%) discontinued

171 pts due to loss of

therapeutic response (34 had


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longer in the pregabalin 300, 450 and 600 mg/day of response were significantly (p < 0.001) longer in

groups than in the matching placebo groups.[40] The pregabalin than placebo recipients as assessed by

time to loss of therapeutic response in the first worsening from baseline in the PGIC responses and

quartile with pregabalin 300, 450 and 600 mg/day FIQ, MOS-Sleep overall sleep problems index,

relative to matched placebo was 122 versus 4 days, MAF, and Short-Form 36 Health Survey (SF-36)

25 versus 7 days and 26 versus 7 days, respectively; physical and mental components scores. Ratings ofthe corresponding proportions of patients with loss much or very much improved on the PGIC were

of therapeutic response by the end of the double- no longer reported by 50% of placebo recipients by

blind phase were 14% versus 42%, 28% versus 50% day 20, whereas a similar loss of response was

and 48% versus 82%.[40] reported by 50% of pregabalin recipients by day 126

(p < 0.0001).[40] Patients receiving pregabalin hadThe results of the sensitivity analyses, whichmedian times to loss of response that were signifi-tested the validity of the primary assumptions, con-cantly (p < 0.0001) longer than those in placebofirmed the superiority of pregabalin over placebo.[40]

recipients as assessed by FIQ total (day 19 vs dayThe Kaplan-Meier estimates of time to loss of thera-14), MOS-Sleep overall sleep problems index (daypeutic response in pregabalin recipients were signif-42 vs day 14), MAF (day 119 vs day 27), SF-36icantly (p < 0.0001) longer than those in placebophysical component (day 49 vs 15) and SF-36recipients in six prespecified sensitivity analysesmental component (day 42 vs day 14) scores. Thethat considered the following alternate scenarios: allamount of paracetamol used as a rescue medicationpatients who withdrew early had a loss of therapeu-did not differ significantly between pregabalin andtic response; all patients who withdrew early main-placebo recipients (165 vs 243 mg/day).[40]tained 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 4. Tolerabilitybeing censored; all patients who had a


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38

20

12

11

8

8

7

7

6

6

5

5

5

5

9

4

12

1

4

2

2

2

2

1

4

1

1

0

0 5 10 15 20 25 30 35 40

Dizziness

Somnolence

Headache

Weight increase

Dry mouth

Blurred vision

Constipation

Fatigue

Peripheral oedema

Euphoric mood

Sinusitis

Increased appetite

Attention disturbance

Balance disorder

Percentage of pts

PL (n = 505)

PRE (n = 1517)

Fig. 4. Tolerability of oral pregabalin (PRE) in patients (pts) with fibromyalgia. Descriptive incidence of pooled adverse events, regardless ofcausality, 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 limited duration.[36,37,41] The occurrence of adverse

in placebo recipients. events of any type increased with increasing dos-

age.[36-38] Where reported,[38-41] treatment-emergentDuring the double-blind phase of the FREEDOMserious adverse events were not considered to betrial in patients who had an initial response to pre-related to pregabalin,[38,40] or were limited to onegabalin, the most common treatment-emergent ad-event of chest pain in a patient receiving pregabalinverse events (incidence 5%) in pregabalin and pla-450 mg/day[39] and two other events (description notcebo recipients were insomnia (both 6%), sinusitis

provided).[41](5% vs 3%), nausea (both 5%), arthralgia (5% vs2%) anxiety (5% vs 2%) and influenza (5% vs 1%). The emergence of adverse events was a reasonReports of adverse events in the double-blind period for discontinuation of treatment in some patients inof the FREEDOM trial represent new onset or clinical trials of pregabalin in fibromyalgia.[36-41]

change in intensity of previously reported adverse Adverse events led to discontinuation of treatmentevents as of randomization.[40] in 19% of pregabalin and 10% of placebo recipients

Although treatment-emergent adverse events in the pooled short-term US trials in fibromy-

were reported in the majority of patients with fibro- algia.[15] In the FREEDOM trial, adverse events led

myalgia receiving pregabalin 150600 mg/day or to the discontinuation of treatment in 19% of pre-

placebo (7894% and 7277% in the short-term US gabalin recipients in the open-label phase, and 17%

trials[36-38]), most events in clinical trials were of of pregabalin and 7% of placebo recipients in themild to moderate intensity[15,36-41] and were often of double-blind phase.[40]



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Dizziness and somnolence are the most frequent Pregabalin has been associated with vision-relat-

ed events, primarily blurred vision.[15] The incidencetreatment-emergent adverse events associated withof blurred vision was numerically higher in pre-pregabalin.[15] The pooled incidences of these eventsgabalin recipients than in placebo recipients in thewere numerically higher in pregabalin recipientspooled results of the short-term US trials in patientsthan in the placebo recipients in the short-term USwith fibromyalgia (figure 4). Blurred vision resolvestrials in patients with fibromyalgia (figure 4).with continued pregabalin treatment in the majorityDuring the open-label phase of the FREEDOM trial,of patients and the clinical significance of vision-dizziness and somnolence were reported in 36% andrelated effects is not currently known.[15]22% of pregabalin 300600 mg/day recipients.[40]

No clinically significant findings on laboratoryDizziness and somnolence are generally reportedevaluations,[36-38,40,41] ECGs,[36-38] or physical[36-38,40]shortly after the initiation of pregabalin therapy,or neurological[36,38,40] examinations were reportedappear to be more frequent at higher dosages, andin clinical trials of pregabalin in patients with fibro-may be transient or persistent. In the three pooled

myalgia. However, across all clinical trials in vari-short-term US trials in patients with fibromy-ous patient populations, elevated creatine kinasealgia,[15] dizziness and somnolence led to discontin-levels, decreased platelet counts and prolonged PRuation in 6% and 3% of pregabalin recipients com-intervals have been associated with pregabalin.[15]pared with


16/19


day if required.[15] If discontinuation of pregabalin is serotonin reuptake inhibitors, analgesics, muscle re-

necessary, the dosage of the drug should be tapered laxants and hypnotics) that have neuromodulatorygradually over a period of at least 1 week.[15] activity.[1-4] Such agents have been used to manage

single symptoms, rather than the condition, as noneDosage reductions of pregabalin are necessary inof these single agents has shown consistent efficacypatients with impaired renal function, as clearanceacross all symptom domains.[48] Available guide-of the drug is directly related to CLCR (section

2.3).[15] Reductions should be based on the patients lines[1-3] were published prior to the recent FDA

CLCR, with the pregabalin dosage reduced by 50% approvals of pregabalin and duloxetine as first-linefor each 50% decrease in CLCR.[15] In addition, as treatments for fibromyalgia.haemodialysis removes pregabalin from the circula- Pregabalin was the first agent to be approved bytion (section 2.3), patients undergoing haemodial- the FDA for the treatment of fibromyalgia.[13] Inysis should receive a single supplemental pregabalin contrast to empirical therapies, monotherapy withdose immediately following each 4-hour haemodial- pregabalin (section 3) has shown a multidimension-ysis treatment.[15] al effect in the treatment of fibromyalgia.[48] Its

Local prescribing information should be con- analgesic and anxiolytic activity in animal modelssulted for further details regarding contraindica- appears to be related to its capacity to selectivelytions, warnings, precautions and use in special popu- bind to the 2 subunit of voltage-gated calciumlations. channels in the CNS, thereby reducing the release of

several neurotransmitters (section 2). The reduction6. Place of Pregabalin in the in neurotransmitter release from neurons in the spi-Management of Fibromyalgia nal cord and brain may be the mechanism of action

responsible for the clinical benefits of pregabalin inFibromyalgia is characterized by chronic and

trials in patients with fibromyalgia.

widespread muscle pain and tenderness, which are Monotherapy with pregabalin is effective in rap-used to distinguish fibromyalgia from other rheu-idly relieving pain in patients with long-standingmatic disorders.[1,4,5,10] The pain, disordered sleepfibromyalgia and moderate to severe levels of painand fatigue associated with fibromyalgia have a(section 3). The proportion of patients with a clini-negative effect on daily life, and are associated withcally significant decrease in pain (i.e. a 30% de-impaired physical functioning, overall health statuscrease in mean pain NRS score) was significantlyand capacity to work.[4,46] Family problems, feelingshigher with pregabalin 300, 450 or 600 mg/day thanof hopelessness and isolation may result from thewith placebo in some, but not all, treatment groupspatients diminished capacity to participate in dailyin short-term trials (section 3.1). Pregabalin is alsolife and social activities, and economic problemsassociated with improvements in several sleep para-may result from the inability of the patient to contin-meters and overall health status (section 3.1).ue to work.[47]

The efficacy of pregabalin is durable in patientsThe goals of treatment of fibromyalgia are towho initially respond to treatment with the drug.alleviate pain, increase restorative sleep and im-The time to loss of therapeutic response was signifi-prove physical function.[11,48] As fibromyalgia is acantly longer in patients receiving pregabalincomplex and difficult-to-treat disorder, a multidis-300600 mg/day than in those receiving placebociplinary approach is suggested by treatment guide-based on a number of efficacy and sensitivity analy-lines.[1-3] Nonpharmacological therapies (e.g. exer-ses in the FREEDOM trial (section 3.2). Although acise, cognitive behavioural therapy and patient edu-relatively large proportion of patients did not res-cation) appear to be helpful in reducing pain andpond to pregabalin therapy in this trial, patients hadtreating other symptoms.[1-3] Recommendations for

severe pain at baseline and, therefore, may not haveempirical pharmacological therapy have been basedbeen able to achieve the demanding predefined cri-on drugs (e.g. tricyclic antidepressants, selective



17/19


teria for response (50% reduction in pain VAS most commonly reported adverse events, were re-

score plus an overall impression of much or very ported in 38% and 20% of pregabalin recipients, but

much improved health). However, according to an only led to discontinuation of treatment in 6% and

editorial,[49] interpretation of the results of long-term 3% of pregabalin recipients. The recommended

trials of pregabalin and other agents in the manage- titration of pregabalin based on response and tolera-

ment of fibromyalgia may be quite difficult due to bility (section 5) may help reduce the incidence of

placebo effects linked to the study design. The en- adverse events. As the adverse events associated

richment design of the FREEDOM trial (i.e. pre- with pregabalin are dose-related and treatment with

gabalin responders in the open-label phase were dosages of 600 mg/day did not appear to confer

enrolled in the double-blind phase) may have com- additional benefit in clinical trials, treatment with

promised the blinding in the pregabalin and placebo pregabalin at dosages >450 mg/day is not recom-

groups, as well as inflating the between-group dif- mended.[15]

ference in pain levels.[49] Of note, the results of the

The pharmacokinetic profile of pregabalin (sec-primary analysis were robust in twopost hoc analy- tion 2.3) is favourable. Unlike the dose-limited ab-ses (section 3.2) performed to account for possible

sorption of gabapentin, absorption of pregabalin isunblinding as the patients moved from open-label to

not saturable, resulting in a linear pharmacokineticdouble-blind treatment.

profile.[20] Pregabalin has a rapid onset of action, as

Fibromyalgia, in common with other chronic shown by the observed onset of efficacy as early as

pain conditions, has been strongly associated with week 1 in clinical trials (section 3.1). Dosage titra-

symptoms of anxiety and depression, which may tion of pregabalin is based on individual patient

have a potential effect on the response to treat- response and tolerability (section 5). The dosage

ment.[50] However, pregabalin appears to be effec- regimen of pregabalin (twice daily with or withouttive in reducing pain regardless of whether patients food) is convenient and uncomplicated, which may

have co-morbid anxiety or depressive symptoms. In aid compliance. The agent is not associated with

a pooled analysis of the three short-term US clinically relevant drug interactions (section 2.3),

trials,[42] although over one-third of patients had which is beneficial in patients who may be receiving

moderate to severe anxiety and over one-quarter had a number of different medications.

moderate to severe depression, there did not appearThe selective serotonin and norepinephrine reup-

to be a significant association between baselinetake inhibitor duloxetine has also been recently ap-

levels of anxiety and depression and the efficacy ofproved by the FDA for the treatment of fibromy-

pregabalin in reducing pain (section 3.1.1). Of note,algia,[14] and has shown efficacy in the treatment of

these trials may underestimate the rates of anxietythis condition in clinical trials.[51,52] Both pregabalin

and depressive symptoms in patients with fibromy-and duloxetine have been effective in treating the

algia, as the trials excluded patients with clinically symptoms of fibromyalgia in only a certain propor-significant or unstable psychiatric conditions, or

tion of patients. Given the complex nature of thewho were unable to withdraw from psychotropic

condition and the number of patients who are refrac-medications.

tory to treatment with the agents, well designed

Adverse events are common with pregabalin, but clinical trials comparing the efficacy of pregabalin

are generally of mild to moderate intensity (section with that of duloxetine may be beneficial in identify-

4). Many patients tolerate the adverse events and ing subgroups of patients with potentially differing

continue with pregabalin treatment; however, ad- pathophysiology who would benefit from treatment

verse events led to discontinuation of pregabalin in with one agent over the other. Evaluations of the

approximately one-fifth of patients in clinical trials. effectiveness of monotherapy or combination ther-

In the pooled results of the three short-term US apy with pregabalin versus other pharmacologicaltrials, for example, dizziness and somnolence, the and nonpharmacological therapies would also be of



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Fibromialgia y Pregabalina