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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 Bibliographical information, including contributory unpublished data, was also requested from the company developing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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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
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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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Pregabalin: A Review 2209
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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Pregabalin: A Review 2211
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-
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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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Pregabalin: A Review 2215
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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Pregabalin: A Review 2217
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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Pregabalin: A Review 2219
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
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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
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Pregabalin: A Review 2221
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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value. Although further study is required, an open- References1. Goldenberg DL, Burckhardt C, Crofford L. Management oflabel prospective trial in 19 patients with fibromy-
fibromyalgia. JAMA 2004 Nov 17; 292 (19): 2388-95algia suggested that pregabalin may be a useful
2. Rooks DS. Fibromyalgia treatment update. Curr Opin Rheu-matol 2007 Mar; 19 (2): 111-7augmentation strategy in patients who partially res-3. Carville SF, Arendt-Nielsen S, Bliddal H, et al. EULAR evi-pond to treatment with quetiapine.[53]
dence-based recommendations for the management of fibro-myalgia syndrome. Ann Rheum Dis 2008 Apr; 67 (4): 536-41Although the direct medical costs (e.g. costs of
4. Chakrabarty S, Zoorob R. Fibromyalgia. Am Fam Physicianvisits to healthcare providers and pharmacological2007 Jul 15; 76 (2): 247-54
and nonpharmacological treatment) associated with 5. American College of Rheumatology. Fibromyalgia [online].Available from URL: http://www.rheumatology.org/public/chronic pain conditions, such as fibromyalgia, canfactsheets/fibromya_new.asp [Accessed 2008 Jun 18]
be high, a substantial burden is also placed on indi- 6. Clauw DJ. Fibromyalgia: update on mechanisms and manage-ment. JCR J Clin Rheumatol 2007; 13 (2): 102-9viduals and society by the indirect costs of absentee-
7. Perrot S. Fibromyalgia syndrome: a relevant recent constructionism and lost productivity.[46] Effective treatment ofof an ancient condition? Curr Opin Support Palliat Care 2008;
the core symptoms of fibromyalgia may allow pa- 2 (2): 122-78. Wolfe F, Smythe HA, Yunus MB, et al. The American Collegetients to return to the workforce or increase theirof Rheumatology 1990 criteria for the classification of fibro-productivity, thereby reducing loss-of-productivitymyalgia: report of the multicenter criteria committee. Arthritis
costs. Pharmacoeconomic analyses from a societal Rheum 1990; 33 (2): 160-729. Wood PB, Holman AJ, Jones KD. Novel pharmacotherapy forperspective based on long-term clinical data are
fibromyalgia. Expert Opin Invest Drugs 2007; 16 (6): 829-41required to provide information on the potential cost 10. Staud R. Treatment of fibromyalgia and its symptoms. Expert
Opin Pharmacother 2007; 8 (11): 1629-42effectiveness of pregabalin relative to other pharma-11. Gur A, Oktayoglu P. Central nervous system abnormalities incological and nonpharmacological therapies in the
fibromyalgia and chronic fatigue syndrome: new concepts intreatment of fibromyalgia. treatment. Curr Pharm Des 2008; 14 (13): 1274-94
12. White KP, Harth M. Classification, epidemiology, and naturalIn conclusion, oral pregabalin has a multidimen-history of fibromyalgia. Curr Pain Headache Rep 2001; 5 (4):
sional effect in the treatment of fibromyalgia. It is 320-913. Pfizers Lyrica receives FDA approval for fibromyalgia basedassociated with rapid and clinically significant im-on expedited review [media release]. Available from URL:
provements in several outcome measures relating to http://www.pfizer.com/news/press_releases/pfizer_press_releases.jsp [Accessed 2008 May 30]core symptoms of this complex syndrome, including
14. Medline Plus. Cymbalta approved for fibromyalgia [online].pain and sleep, in patients with long-standing fibro-Available from URL: http://www.nlm.nih.gov/medlineplus/
myalgia. Pregabalin is also associated with improve- new/fullstory_65861.html [Accessed 2008 Jun 18]15. Lyrica (pregabalin) capsules: US prescribing information. Newments in overall health status. The beneficial effects
York: Pfizer Inc., 2007 Junof pregabalin are durable in patients with an initial
16. European Medicines Agency. Lyrica (pregabalin): summary ofresponse to the drug. The most common adverse product characteristics [online]. Available from URL: http://
www.emea.europa.eu/humandocs/Humans/EPAR/lyrica/lyri-events associated with the drug are dizziness andca.htm [Accessed 2008 May 30]
somnolence, which are generally mild to moderate17. Frampton JE, Foster RH. Pregabalin in the treatment of posther-petic neuralgia. Drugs 2005; 65 (1): 111-8in intensity and are tolerated by many patients.18. Lauria-Horner BA, Pohl RB. Pregabalin: a new anxiolytic.Pregabalin is, therefore, a valuable option in the
Expert Opin Investig Drugs 2003; 12 (4): 663-72first-line treatment of patients with fibromyalgia. 19. Bryans JS, Wustrow DJ. 3-Substituted GABA analogs with
central nervous system activity: a review. Med Res Rev 1999Mar; 19 (2): 149-77
20. Gajraj NM. Pregabalin: its pharmacology and use in pain man-Disclosureagement. Anesth Analg 2007; 105 (6): 1805-15
21. Belliotti TR, Capiris T, Ekhato IV, et al. Structure-activityThe preparation of this review was not supported by any relationships of pregabalin and analogues that target the 2-
protein. J Med Chem 2005 Apr 7; 48 (7): 2294-307external funding. During the peer review process, the manu-22. Dooley DJ, Taylor CP, Donevan S, et al. Ca2+ channel 2facturer of the agent under review was offered an opportunity
ligands: novel modulators of neurotransmission. Trendsto comment on this article. Changes resulting from comments
Pharmacol Sci 2007; 28 (2): 75-82received were made on the basis of scientific and editorial 23. Taylor CP, Angelotti T, Fauman E. Pharmacology and mecha-merit. nism of action of prebabalin: the calcium channel 2- (al-
2008 Adis Data Information BV. All rights reserved. Drugs 2008; 68 (15)
7/28/2019 Fibromialgia y Pregabalina
19/19
Pregabalin: A Review 2223
pha2-delta) subunit as a target for antiepileptic drug discovery. 40. Crofford LJ, Mease PJ, Simpson SL, et al. Fibromyalgia relapseEpilepsy Rev 2007; 73 (2): 173-50 evaluation and efficacy for durability of meaningful relief
(FREEDOM): a 6-month, double-blind, placebo-controlled24. Perucca E. Clinically relevant drug interactions with antiepilep-trial with pregabalin. Pain 2008 Jun; 136 (3): 419-31tic drugs. Br J Clin Pharmacol 2005; 61 (3): 246-55
41. Florian H, Young Jr JP, Haig G, et al. Efficacy and safety of25. Ben-Menachem E. Pregabalin pharmacology and its relevancepregabalin as long-term treatment of pain associated withto clinical practice. Epilepsia 2004; 45 Suppl. 6: 13-8fibromyalgia: a 1-year, open-label study [abstract no. 1523].26. Field MJ, Cox PJ, Stott E, et al. Identification of the 2--1Arthritis Rheum 2007 Sep 1; 56 (9 Suppl.): S602subunit of voltage-dependent calcium channels as a molecular
42. Arnold L, Pauer L, Whalen E, et al. Pain changes in pregabalin-target for pain mediating the analgesic actions of pregabalin.treated (Lyrica) fibromyalgia patients associate with anxietyProc Natl Acad Sci U S A 2006 Nov 14; 103 (46): 17537-42and depression changes [abstract no. 290]. J Pain 2008 Apr; 927. Beidler D, Kinsora J, El-Kattan A, et al. Pregabalin demonstra-(4 Suppl. 2). Plus poster presented at the 27th Annual Scien-tes activity in animal models of pain, sleep, and anxiety thattific Meeting of the American Pain Society; 2008 May 8-10;reflect the symptoms and comorbidities associated with fibro-Tampa (FL)myalgia [abstract no. 522]. Arthritis Rheum 2004 Sep; 50 (9
43. Arnold L, Leon T, Whalen E, et al. Treatment with pregabalin isSuppl.): S250associated with improvement in pain regardless of the presence28. Field MJ, Oles RJ, Singh L. Pregabalin may represent a novelof baseline symptoms of anxiety or depression: findings from 3class of anxiolytic agents with a broad spectrum of activity.randomized clinical trials [abstract no. THU358]. Ann RheumBr J Pharmacol 2001 Jan; 132 (1): 1-4Dis 2008; 67 Suppl. II: 249. Plus poster presented at the29. Kubota T, Fang J, Meltzer LT, et al. Pregabalin enhances Congress of the European League Against Rheumatism; 2008
nonrapid eye movement sleep. J Pharmacol Exp Ther 2001 Jun 11-14; ParisDec; 299 (3): 1095-105
44. Farrar JT, Young Jr JP, LaMoreaux L, et al. Clinical importance30. Hindmarch I, Trick L, Ridout F. A double-blind, placebo- and of changes in chronic pain intensity measured on a 11-point
positive-internal-controlled (alprazolam) investigation of the numerical rating scale. Pain 2001; 94 (2): 149-58cognitive and psychomotor profile of pregabalin in healthy
45. Dunkl PR, Taylor AG, McConnell GG, et al. Responsiveness ofvolunteers. Psychopharmacology (Berl) 2005 Dec; 183 (2):
fibromyalgia clinical trial outcome measures. J Rheumatol133-43
2000; 27 (11): 2683-9131. Hindmarch I, Dawson J, Stanley N. A double-blind study in
46. White LA, Birnbaum HG, Kaltenboeck A, et al. Employees withhealthy volunteers to assess the effects on sleep of pregabalin
fibromyalgia: medical comorbidity, healthcare costs, and workcompared with alprazolam and placebo. Sleep 2005 Feb 1; 28
loss. J Occup Environ Med 2008; 50 (1): 13-24(2): 187-93
47. Forseth K, Gran JT. Management of fibromyalgia: what are32. de Haas S, Otte A, de Weerd A, et al. Exploratory polysomno-
the best treatment choices? Drugs 2002; 62 (4): 577-92
graphic evaluation of pregabalin on sleep disturbance in pa- 48. Lawson K. Pharmacological treatments of fibromyalgia: dotients with epilepsy. J Clin Sleep Med 2007 Aug 15; 3 (5): 473-complex conditions need complex therapies? Drug Discov8Today 2008 Apr; 13 (7-8): 333-40
33. Busch JA, Strand JC, Posvar EL, et al. Pregabalin (CI-1008)49. Staud R, Price DD. Long-term trials of pregabalin and duloxe-single-dose pharmacokinetics and safety tolerance in healthy
tine for fibromyalgia symptoms: how study designs can affectsubjects after administration of pregabalin solution or capsuleplacebo factors. Pain 2008 Jun; 136 (3): 232-4doses [abstract no. 2.108]. Epilepsia 1998; 39 Suppl. 6: 58
50. Arnold LM, Crofford LJ, Martin SA, et al. The effect of anxiety34. Corrigan BW, Pool WF, Posvar EL, et al. Metabolic dispositionand depression on improvements in pain in a randomized,of pregabalin in healthy volunteers [abstract no. PI-68]. Clincontrolled trial of pregabalin for treatment of fibromyalgia.Pharmacol Ther 2001 Feb; 69 (2): P18Pain Med 2007; 8 (8): 633-8
35. Randinitis EJ, Posvar EL, Alvey CW, et al. Pharmacokinetics of51. Arnold LM, Pritchett YL, DSouza DN, et al. Duloxetine for thepregabalin in subjects with various degrees of renal function.
treatment of fibromyalgia in women: pooled results from twoJ Clin Pharmacol 2003 Mar; 43 (3): 277-83randomized, placebo-controlled clinical trials. J Womens
36. Crofford LJ, Rowbotham MC, Mease PJ, et al. Pregabalin forHealth (Larchmt) 2007 Oct; 16 (8): 1145-56
the treatment of fibromyalgia syndrome: results of a random- 52. Russell IJ, Mease PJ, Smith TR, et al. Efficacy and safety ofized, double-blind, placebo-controlled trial. Arthritis Rheumduloxetine for treatment of fibromyalgia in patients with or2005 Apr; 52 (4): 1264-73without major depressive disorder: results from a 6-month,
37. Mease PJ, Russell IJ, Arnold LM, et al. A randomized, double-randomized, double-blind, placebo-controlled, fixed-dose
blind, placebo-controlled, phase III trial of pregabalin in thetrial. Pain 2008 Jun; 136 (3): 432-44
treatment of patients with fibromyalgia. J Rheumatol 200853. Calandre EP, Morillas-Arques P, Rodriguez-Lopez CM, et al.Mar; 35 (3): 502-14
Pregabalin augmentation of quetiapine therapy in the treatment38. Arnold LM, Russell IJ, Diri EW, et al. A 14-week, randomized,
of fibromyalgia: an open-label, prospective trial. Pharmacop-double-blinded, placebo-controlled monotherapy trial of pre-
sychiatry 2007 Mar; 40 (2): 68-71gabalin in patients with fibromyalgia. J Pain 2008 Sep; 9 (9):792-805
39. Pauer L, Danneskiold-Samsoe B, Jesperson A, et al. Pregabalin Correspondence: Katherine A. Lyseng-Williamson, Woltersfor management of fibromyalgia (FM): a 14-week randomized,
Kluwer Health | Adis, 41 Centorian Drive, Private Bagdouble-blind, placebo-controlled monotherapy trial (study
65901, Mairangi Bay, North Shore 0754, Auckland, NewA0081100) [abstract no. THU0382]. Ann Rheum Dis 2008; 67 Zealand.Suppl. II: 256. Plus poster presented at the Congress of theEuropean League Against Rheumatism; 2008 Jun 11-14; Paris E-mail: demail@adis.co.nz
2008 Adis Data Information BV. All rights reserved. Drugs 2008; 68 (15)
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