FULL Pregabalin (Lyrica) REVIEW 1

Pregabalin (Lyrica)
NPS RADAR | APRIL 2013
1
FULL
REVIEW
An alternative
adjuvant analgesic
for refractory
neuropathic pain
Pregabalin (Lyrica)
for neuropathic pain
(pre-GAB-a-lin)
KEY POINTS
Pregabalin appears to have similar efficacy to that of amitriptyline
and gabapentin for neuropathic pain
Pregabalin is superior in efficacy to placebo and appears to be non-inferior in efficacy
and safety to amitriptyline and gabapentin (from indirect comparisons).
Consider initial treatment with another agent, such as a tricyclic
antidepressant, before pregabalin
Pregabalin is only PBS listed for people with refractory neuropathic pain not controlled
by other drugs (Authority Required).
Dizziness and drowsiness are common dose-dependent adverse events
In trials these were the most common adverse effects causing people to stop pregabalin.
Dosage reduction is required in people with impaired renal function
Assess renal function in people with diabetic neuropathy before starting pregabalin treatment.
PBS listing
Who is it for?
Authority required (Streamlined)
Pregabalin is a treatment option for people
with refractory neuropathic pain who have not
responded to other drugs. Use with caution in
people with renal impairment, as pregabalin
is renally excreted.1
Refractory neuropathic pain not controlled
by other drugs.
May be prescribed by nurse practitioners
Authorised nurse practitioners may prescribe
this medicine. See the Pharmaceutical Benefits
Scheme (PBS) website for more information
on nurse practitioner PBS prescribing.
ADDITIONAL
INFORMATION
www.pbs.gov.au/info/
healthpro/explanatorynotes/section1/nursepractitioner
What is it?
Pregabalin is a structural analogue of the
neurotransmitter GABA.1 It has analgesic,
anticonvulsant, anxiolytic and sleep-modulating
activities and is indicated for treatment of
epilepsy and neuropathic pain. 2,3 It has a
similar pharmacological action to that of
gabapentin. 2,4 However, it should be noted
that gabapentin is not PBS reimbursed for
neuropathic pain.
Where does it fit?
There is no generally accepted ‘stepwise’
approach to treating neuropathic pain. There
is an array of drugs with limited evidence for
differences in efficacy, and often with troublesome
adverse effects. Drug therapy is best used as
part of a multifaceted, multidisciplinary, active
self-management approach to the physical,
psychological, social and vocational impacts
of neuropathic pain. 5 Assess the nature of the
pain experience and inform people of realistic
outcomes with treatment.6,7 The primary goal in
most cases is to make the pain tolerable — not
usually to eliminate the pain.6 Aim for medium-term
drug therapy with a drug holiday after 6 months.
Patients who relapse during a drug holiday can
resume treatment.
NPS MedicineWise
Pregabalin (Lyrica)
NPS RADAR | APRIL 2013
2
Guidelines recommend starting drug therapy
for neuropathic pain with a TCA (amitriptyline or
nortriptyline) or an antiepileptic agent (gabapentin
or pregabalin).6–12 The dose of the drugs can be
escalated at weekly intervals if tolerated, but it
may take several weeks to achieve clinical efficacy.
Consider initial therapy with
amitriptyline or nortriptyline
TCAs are an established first-line treatment
option for neuropathic pain but are not approved
by the Therapeutic Goods Administration (TGA)
for this indication.6-12 Amitriptyline is the most
studied TCA for neuropathic pain.13 TCAs exhibit
significant adverse effects that limit their clinical
use, particularly in elderly people.13 Anticholinergic
adverse events, such as dry mouth, constipation
and urinary retention, are common.13 In addition
they may cause serious cardiovascular adverse
effects, including postural hypotension, heart
block and arrhythmias.13
Gabapentin is effective for treating
neuropathic pain
Guidelines recommend gabapentin for the
treatment of neuropathic pain.6-12 However, it is
not reimbursed by the PBS for this indication.
In a meta-analysis gabapentin was demonstrated
to be effective for the treatment of a variety
of neuropathic pain conditions.14 The number
Table 1.
Efficacy outcomes
with different doses
of pregabalin for
the treatment
of postherpetic
neuralgia and diabetic
neuropathy, compared
with placebo15
Pregabalin
daily dose
Number of
studies
Participants
needed to treat (NNT) to benefit, as measured by
the Initiative on Methods, Measurement, and Pain
Assessment in Clinical Trials (IMMPACT) definition,
were 6.8 (95% confidence interval [CI] 5.6 to 8.7)
for substantial pain relief (50% over baseline) and
5.8 (95% CI 4.8 to 7.2) for moderate pain relief
(35% over baseline).14
Consider pregabalin for neuropathic
pain refractory to other drugs
In clinical trials pregabalin provided significant pain
relief (see Table 1) and improved quality of sleep
in both postherpetic neuralgia and painful diabetic
neuropathy.15 Pregabalin has dose-dependent
clinical efficacy and appears not to be effective
at 150 mg/day for diabetic neuropathy.15
Preliminary evidence suggests that pregabalin
may be effective in the treatment of trigeminal
neuralgia.16–18 However, further clinical trial data
are required before it can be recommended for
this indication. The anticonvulsant carbamazepine
remains the drug of choice for trigeminal neuralgia.6,8
Consider combination therapy
A significant proportion of people with neuropathic
pain will not benefit from treatment with a
single medication, even when administered at its
maximum tolerated dose.7,19 Evidence suggests
that at least 45% of people with neuropathic pain
concurrently receive two or more drugs to treat
Relative benefit* (95% CI)
At least 50% pain relief NNT
(95% CI)†
Postherpetic neuropathic pain
150 mg
3
527
2.3 (1.6 to 3.4)
6.9 (4.8 to 13)
300 mg
4
713
2.5 (1.9 to 3.4)
5.1 (3.9 to 7.4)
600 mg
4
732
2.7 (2.1 to 3.5)
3.9 (3.1 to 5.1)
Diabetic neuropathic pain
150 mg
2
359
1.1 (0.8 to 1.6)
NA‡
300 mg
4
823
1.5 (1.2 to 1.8)
7.5 (5.1 to 14)
600 mg
6
1360
1.7 (1.5 to 2.0)
5.0 (4.0 to 6.6)
* Relative to placebo
† NNT were calculated from the combined results of clinical trials with different durations (4–14 weeks)
‡ Not effective at 150 mg
NPS MedicineWise
Pregabalin (Lyrica)
NPS RADAR | APRIL 2013
3
EVIDENCE SNAPSHOT
WHAT IS KNOWN ABOUT
THIS DRUG?
Pregabalin is a structural analogue
of the neurotransmitter gammaaminobutyric acid (GABA). It appears
to have a similar spectrum of benefits
and harms to that of other adjuvant
analgesics used to treat neuropathic
pain. It is clinically superior to
placebo, and indirect comparisons
suggest it is non-inferior for
efficacy and safety to amitriptyline
and gabapentin.
AREAS OF UNCERTAINTY
WHAT DOES NPS SAY?
There are no head-to-head trials
comparing the efficacy of pregabalin
with that of other drugs for
neuropathic pain. Information
about its use in people with
head and neck pain is lacking.
Pregabalin is an alternative treatment
for people with neuropathic pain
that has not responded to other
drugs. Consider initial treatment with
another adjuvant analgesic, such as
a tricyclic antidepressant (TCA),
before pregabalin. Be aware that
dizziness and drowsiness are
common dose-dependent adverse
events associated with pregabalin
and may persist until treatment
is stopped.
their pain.19 Combining two or more different drugs
may improve analgesic efficacy and reduce overall
adverse events if synergistic interactions allow
dose reductions of combined drugs.19 However,
combinations of medicines can be associated
with increased adverse events.19
A specific combination of treatments cannot be
recommended due to the limited number of studies
for any combination therapy, as well as other study
factors, such as the limited trial size and duration.19
Clinical studies of pregabalin in combination with
an antidepressant, a cyclo-oxygenase-2 (COX-2)
inhibitor or an opioid have shown positive responses
greater than the respective monotherapies in
diabetic neuropathy and postherpetic neuralgia
(five positive trials and one negative trial). 20
Refractory severe neuropathic pain
ADDITIONAL
INFORMATION
Refer to this review at
www.npsradar.org.au for
more information about
TGA approval status and
PBS listing restrictions
for prescription drugs for
adults with neuropathic
pain: (December 2012)
Assistance from a multidisciplinary pain service
may be required for refractory, severe neuropathic
pain, as treatment options are complex. 5
The TGA has not approved some of the drugs
recommended in guidelines for a neuropathic
pain indication and most are not subsidised
by the PBS for neuropathic pain.6–12
Tramadol can be considered as a third-line
treatment for refractory neuropathic pain.6–12
However, other opioids are not recommended
without further pain-medicine specialist input due
to the problems with tolerance and dependence.6-12
There is limited evidence for use of selective
serotonin reuptake inhibitors or serotoninnoradrenaline reuptake inhibitors in the treatment
of neuropathic pain, and further research is
required to establish their role.13
How does it compare?
Pregabalin is superior to placebo for
the treatment of neuropathic pain
A meta-analysis of randomised placebocontrolled trials demonstrated that pregabalin
(300 mg, 450 mg and 600 mg daily) significantly
reduced subjective pain compared with placebo
for neuropathic conditions.15 Pregabalin
administered as 150 mg/day was generally
ineffective for diabetic neuropathic pain.15
After pregabalin treatment a minority of
patients had substantial benefit (at least 50%
pain relief), and more had moderate benefit
(at least 35% pain relief).15 After treatment with
pregabalin (300–600 mg daily) the Patient
Global Impressions of Change (PGIC) rating
of much or very much improved was achieved
in about 35% of patients with postherpetic
neuralgia and 50% of those with painful diabetic
neuropathy.15 At all doses a significant proportion
of patients had no, or trivial, benefit, or
discontinued because of adverse events.15
NPS MedicineWise
Pregabalin (Lyrica)
NPS RADAR | APRIL 2013
4
Limited evidence comparing pregabalin
with amitriptyline and gabapentin
There are no adequately powered direct headto-head trials comparing pregabalin with other
drugs. There are indirect comparisons of pregabalin
with amitriptyline and gabapentin using placebo
as the common comparator. 21 However, indirect
comparisons have numerous limitations, as they
compare different patient populations, primary
outcomes and pain measurement scales.
The PBAC noted that indirect comparisons supported
the conclusion that pregabalin was clinically no
worse than amitriptyline and gabapentin. 21
The efficacy and safety of pregabalin and
amitriptyline were demonstrated to be comparable
in two head-to-head clinical trials in patients with
diabetic peripheral neuropathy, but these were
not powered to detect either superiority or noninferiority of pregabalin versus amitriptyline. 22,23
A 36-day head-to-head dose titration trial in patients
with diabetic peripheral neuropathy compared
pregabalin (300 mg followed by 600 mg, n = 24),
duloxetine (60 mg followed by 120 mg, n = 23) and
amitriptyline (50 mg followed by 75 mg, n = 27).23
All treatments improved subjective pain versus
placebo as assessed by the primary outcome
measure, the Brief Pain Inventory, and also the
secondary outcome measure, the short-form McGill
visual analogue scale, with no difference between
treatments after 1 week of treatment. 23
Pregabalin appears to have some distinct
pharmacokinetic advantages over gabapentin,
with higher bioavailability, more rapid absorption
and increased binding affinity.4 However, headto-head trials are needed to provide evidence
supporting the use of pregabalin over gabapentin
in the treatment of neuropathic pain.
Safety issues
Pregabalin is generally well tolerated and is
associated with dose-dependent adverse events
that are mild to moderate and usually transient. 2
As pregabalin alters neurotransmission, it can
cause a variety of neurological adverse events.
NPS MedicineWise
Common adverse effects reported in at least 3%
of all patients treated with pregabalin include:12
dizziness
drowsiness
blurred vision
fatigue
weight gain
dry mouth
headache
impaired balance
peripheral oedema.
Report suspected adverse reactions to the TGA
online (www.ebs.tga.gov.au) or by using the ‘Blue
Card’ distributed three times a year with Australian
Prescriber. For information about reporting adverse
reactions, see the (www.tga.gov.au).
Dizziness and drowsiness: the
most common reason for stopping
pregabalin therapy
In clinical trials dizziness and drowsiness were
commonly reported (28–36% and 20–24%
of patients, respectively, taking pregabalin
300 mg/day).1 Both adverse effects occurred
more often at higher doses and were the most
common reasons for stopping pregabalin.1
About one-third of people reported dizziness
and about half reported drowsiness persisting
throughout therapy.1
Weight gain
Weight gain occurred more frequently in
patients treated with pregabalin compared
with placebo.1 This dose-dependent side effect
may be problematic for patients, such as those
with diabetes, who may need to adjust
hypoglycaemic medications.1
Occurrence of peripheral oedema
In randomised controlled trials, peripheral
oedema was seen more frequently in people
with neuropathic pain treated with pregabalin
than in those in the control group.1,24 This may be
a particular concern with the higher incidence of
peripheral oedema in people with diabetes. 24
Pregabalin (Lyrica)
NPS RADAR | APRIL 2013
5
Congestive heart failure
There have been postmarketing reports
of congestive heart failure in some people
receiving pregabalin.1
Depression and anxiety
Neuropathic pain can be severe and unrelenting;
thus it is important to recognise and treat
comorbidities such as anxiety and depression.6 In
addition, anticonvulsant drugs, including pregabalin,
increase the risk of suicidal thoughts or behaviours
in people using them for any indication. 25,26 Monitor
people treated with pregabalin for the emergence
or worsening of depression, suicidal thoughts or
self-harm behaviour and/or any unusual changes
in mood or behaviour.1
ADDITIONAL
INFORMATION
More information
available at
www.hnehealth.
nsw. gov.au/pain/
health_professionals/
assessment_tools
Reason for PBS listing
The PBAC recommended pregabalin for listing
on the basis of an indirect comparison with
amitriptyline and gabapentin with placebo
as the common comparator. The PBAC
accepted that pregabalin was clinically
superior to placebo and clinically no worse
than amitriptyline or gabapentin. 21
The PBAC recommended listing of pregabalin
on the basis of acceptable cost-effectiveness
compared with placebo in people with
uncontrolled neuropathic pain. It noted
the clinical need for an alternative to
current treatments for neuropathic pain. 21
ADDITIONAL
INFORMATION
Available at
www.nps.org.au/
medicines/lyrica
A key issue identified by the PBAC was
economic uncertainty from the potential
for pregabalin use outside the restriction.
They considered that it was essential that
the drug utilisation subcommittee (DUSC)
review usage 12 months after PBS listing. 21
Dosing issues
Start with 75 mg twice a day for 3–7 days. If required,
increase dose to 150 mg twice a day after 3–7 days,
to a maximum of 300 mg twice a day after another
7 days.1 It may take several weeks to achieve maximal
effect with pregabalin. If improvement is satisfactory
continue treatment and consider gradually reducing
the dose over time if improvement is sustained.9
Discontinue pregabalin if it does not improve
symptoms or is not tolerated by tapering the dose
over a minimum of 1 week, or longer depending
on the dose and duration of therapy.1 Abrupt
withdrawal may result in adverse events, including
insomnia, headache, nausea, anxiety, hyperhidrosis
and diarrhoea.1
Adjust the dose in renal impairment: refer to the
product information for details.1
Conduct early and regular clinical reviews
Due to the refractory nature of neuropathic
pain, conduct early and regular clinical reviews
to monitor the effectiveness of the chosen
treatment. 9 The review should assess:
pain (utilise multidimensional tools, such
as the Brief Pain Inventory, that provide
information about pain history, intensity
and associated disability)
adverse events
daily activities (e.g. ability to work or drive)
mood (particularly if the person may be
depressed and/or anxious)
quality of sleep
subjective, overall self-reported improvement
in pain (e.g. using PGIC).9
Information for patients
Discuss the Lyrica consumer medicine
information (CMI) leaflet with the patient
and inform about common side effects such as
dizziness and drowsiness. Monitor for weight
gain and advise that constipation, diarrhoea,
nausea, headache, weight gain, dry mouth or
blurred vision may occur, and that, if they are
affected, not to drive or operate machinery.
Advise patients not to stop taking pregabalin
suddenly. Stopping suddenly may cause
anxiety, insomnia, headache, sweating,
nausea and diarrhoea.
Advise that it may take several weeks to achieve
maximal effect for postherpetic neuralgia.
NPS MedicineWise
Pregabalin (Lyrica)
NPS RADAR | APRIL 2013
6
REFERENCES
1.
Pfizer Australia. Pregabalin (Lyrica) product
information. 2011. https://www.ebs.tga.gov.au/ebs/
picmi/picmirepository.nsf/pdf?OpenAgent&id=CP2010-PI-04219-3
11.
Finnerup NB, et al. Pain 2010;150:573–81.
12.
Australian Medicines Handbook. Analgesics.
http://amh.hcn.com.au/ (accessed 17 October 2012).
2.
Gajraj NM. Anesth Analg 2007;105:1805–15.
13.
3.
Australian Government Department of Health
and Ageing, Therapeutics Goods Administration.
Australian Register of Therapeutic Goods (ARTG).
Public Summary LYRICA pregabalin. 2012. https://
www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs%
2FPublicHTML%2FpdfStore.nsf&docid=B9871D6C4
363698ACA2578CD00424892&agid=(PrintDetails
Public)&actionid=1 (accessed 5 December 2012).
Saarto T, Wiffen PJ. Cochrane Database Syst
Rev 2007:CD005454.
14.
Moore RA, et al. Cochrane Database Syst
Rev 2011:CD007938.
15.
Moore RA, et al. Cochrane Database Syst
Rev 2009:CD007076.
16.
Perez C, et al. J Clin Pharmacol 2009;49:582–90.
17.
Perez C, et al. Cephalalgia 2009;29:781–90.
18.
Obermann M, et al. Cephalalgia 2008;28:174–81.
19.
Chaparro LE, et al. Cochrane Database Syst Rev
2012;7:CD008943.
4.
Bockbrader HN, et al. Clin Pharmacokinet
2010;49:661–9.
5.
Australian Pain Society. Evidence-based
recommendations for the pharmacological
management of neuropathic pain. Position
statement, June 2008. http://www.apsoc.org.au/
owner/files/cz4s7w.pdf (accessed 20 October 2012).
6.
Moulin DE, et al. Pain Res Manag 2007;12:13–21.
7.
Dworkin RH, et al. Mayo Clin Proc 2010;85:S3–14.
8.
Attal N, et al. Eur J Neurol 2010;17:1113–e88.
9.
National Institute for Health and Clinical Excellence
(NICE). Neuropathic pain: The pharmacological
management of neuropathic pain in adults in
non-specialist settings. Clinical Guideline 96.
2010; 17 August 2012. http://www.nice.org.uk/
guidance/CG96 (accessed 20 October 2012).
10.
eTG complete. Neuropathic pain: treatment. 2012.
http://etg.hcn.com.au/ (accessed 17 October 2012).
20. Vorobeychik Y, et al. CNS Drugs 2011;25:1023–34.
21.
Pharmaceutical Benefits Advisory Committee.
Pregabalin, capsules, 25 mg, 75 mg,
150 mg and 300 mg, Lyrica – March 2012.
Public summary document. PBAC, 2012.
http://www.pbs.gov.au/info/industry/listing/
elements/pbac-meetings/psd/2012-03/
pregabalin (accessed 22 October 2012).
22. Bansal D, et al. Diabetic Med 2009;26:1019–26.
23. Boyle J, et al. Diabetes Care 2012.
24. Zaccara G, et al. Eur J Clin Pharm 2012;68:903–12.
25. Andersohn F, et al. Neurology 2010;75:335–40.
26. Mutschler J, et al. Pharmacopsychiatry 2011;44:119.
Updated April 2013 to reflect PBS listing effective from 1 March 2013.
First published: December 2012.
The information contained in NPS RADAR is derived from a critical analysis of a wide range of authoritative evidence
and is current at the time of publication. Any treatment decisions based on the information provided in NPS RADAR
should be made in the context of the clinical circumstances of each patient.
NPS RADAR articles may be updated when there is new evidence about safety or efficacy, or in case of regulatory
or PBS listing changes.
Please refer to www.npsradar.org.au for the most recent version as well as any supplementary information.
NPS MedicineWise