21

Treatment of Neuropathic Pain: Antiepileptic

and Antidepressant Drugs
Ian Gilron, MD, MSc, FRCPC

Department of Anesthesiology and Perioperative Medicine and Department of Biomedical and Molecular Sciences,
Queens University and Kingston General Hospital, Kingston, Ontario, Canada

Educational Objectives
1. To review the mechanisms and eects of antiepileptic and antidepressant drugs in neuropathic pain.
2. To review clinically relevant pharmacokinetics and
pharmacodynamics of antiepileptic and antidepressant drugs.
3. To describe the clinical evidence base supporting
the use of antiepileptic and antidepressant drugs in
neuropathic pain.

Introduction

neuropathy, cancer-related neuropathy, postherpetic

neuralgia, HIV-related neuropathy, spinal cord injury,
multiple sclerosis, central poststroke pain, trigeminal
neuralgia, post-traumatic/postsurgical neuropathic
pain, and complex regional pain syndrome type II,
among others [30]. A very large proportion of clinical
drug trials in neuropathic pain have been conducted
specically in patients with painful diabetic neuropathy and postherpetic neuralgia [23], leaving other
prevalent neuropathic pain conditions such as lumbar
radiculopathy relatively understudied with respect to
systemic drug treatment [41].

Antiepileptic Drugs
Neuropathic Pain
Neuropathic pain was originally dened by the International Association for the Study of Pain (IASP), in
1994, as pain initiated or caused by a primary lesion
or dysfunction in the nervous system [57]. In 2008,
Treede et al. proposed a redenition to pain arising
as a direct consequence of a lesion or disease aecting
the somatosensory system [78]. Since then, the IASP
has revised the 1994 denition to pain caused by a lesion or disease of the somatosensory nervous system
[36]. Neuropathic pain, which has been reported in
710% of the general population in developed countries [79], includes a diverse group of clinical conditions such as cervical or lumbar radiculopathy, diabetic
Pain 2014: Refresher Courses, 15th World Congress on Pain
Srinivasa N. Raja and Claudia L. Sommer, editors
IASP Press, Washington, D.C. 2014

Pharmacological approaches to the treatment of seizures and epilepsy in the early 1900s [73] have led to
the introduction of a diverse group of antiepileptic
drugs into clinical practice. Initial observations of pain
reduction with phenytoin in the treatment of trigeminal
neuralgia [7] led to extensive preclinical and clinical investigation on the contribution of antiepileptic drugs to
pain management [15,87]. As research eorts have continued, newer applications of antiepileptic drugs have
been demonstrated in a wide variety of pain conditions.

Antidepressant Drugs
Over half a century ago, observations of analgesic
efficacy of the antidepressant drug, imipramine, in
225

226
neuropathic [86] and rheumatic [45] conditions led
to the clinical development of antidepressant drugs
for the treatment of pain. More rigorous evaluations that demonstrated analgesia with antidepressant drugs in neuropathic pain patients without clinical depression [83] provided evidence that analgesic
mechanisms of these drugs could be independent of
their antidepressant effects. Since these early clinical investigations, analgesic efficacy of antidepressants has been evaluated in dozens of randomized
controlled trials (RCTs). Other than nonsteroidal
anti-inflammatory drugs (NSAIDs) and opioids, antidepressants have since become the next most widely
used class of drugs for the treatment of pain [51,84].
This chapter will review antiepileptics and antidepressants in the management of neuropathic pain,
with the exclusion of headache disorders, which are discussed elsewhere.

Pharmacological Mechanisms

Ian Gilron
Table I
Pharmacological classification of antiepileptic drugs
Mechanism Relevant to Pain Treatment
Antiepileptic
Drug

Na+ Channel
Blockade

Ca2+ Channel
Blockade

Glutamate
Suppression

First Generation
Benzodiazepines

Carbamazepine

++

Ethosuximide

Phenobarbital

Phenytoin

++

Primidone

Valproic acid

Felbamate

++

Gabapentin

Lacosamide

Second Generation

Lamotrigine

++

++

Levetiracetam

Oxcarbazepine

++

Pregabalin

Tiagabine

Topiramate

++

Antiepileptic Drugs

Vigabatrin

Drugs that suppress experimental and clinical seizures, dened as anticonvulsant or antiepileptic drugs,
are classied as rst-generation antiepileptics (e.g.,
benzodiazepines, carbamazepine, ethosuximide, phenobarbital, phenytoin, primidone, and valproic acid),
which were introduced between 1910 and 1970, and
second-generation antiepileptics (e.g., felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin,
and zonisamide), which were introduced more recently
[48]. In addition to reducing pain intensity, some antiepileptics also improve sleep [66] and reduce anxiety
[63], which are of clinical relevance to the management
of chronic pain. Multiple pharmacological mechanisms
(see Table I) have been elucidated for most antiepileptic drugs, including sodium channel blockade, calcium
channel blockade, and suppression of glutamatergic
transmission and/or -aminobutyric acid (GABA)ergic
modulation [15].

Zonisamide

++

++

Antidepressant Drugs
Antidepressant drugs include a wide array of chemical agents that can be characterized by chemical
structure and/or major pharmacological mechanism
and broadly include the older tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors

Source: [65].
?, currently unclear whether this mechanism is involved.

(SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs),
and others. Regardless of specic molecular mechanisms listed below, the clinical rationale for using antidepressants in the management of chronic pain may
also include treatment of comorbid depression and
sleep disturbance as well as reduction of pain intensity
[75]. A large body of preclinical research has pointed
to several putative analgesic mechanisms of antidepressant drugs (see Table II). These include increased
supraspinal availability of norepinephrine (thought to
enhance descending inhibitory bulbospinal control),
activation of endogenous - and -opioid receptors,
sodium channel blockade, and N-methyl-D-aspartate
(NMDA) receptor inhibition, among others [58].

Trial-Based Evidence
of Analgesic Ecacy
Attempts to describe ecacy of a given treatment often involve systematic review of published high-quality clinical trials (RCTs) and meta-analysis in order to

Antiepileptics and Antidepressants for Neuropathic Pain

227

Table II
Putative analgesic mechanisms of antidepressant drugs
Pain
Mechanisms
5-HT mediated

Comments
5-HT availability
Blockade of neural reuptake
Inhibition of MAO
5-HT1A receptors
5-HT2 receptors

5-HT3 receptors
Norepinephrine
mediated

Norepinephrine availability
Blockade of neural reuptake
Inhibition of MAO
2-Adrenoceptors

1-Adrenoceptors

Dopamine
mediated
Opioid
mediated

Ion channels
Na+ channels
K+ channels
Ca2+ channels

Adenosine
NMDA
receptors
GABAB
receptors
Substance P
P2X receptors
Inflammatory
and immune
parameters

1- and 2-adrenoceptors
Dopamine availability
Blockade of neural reuptake
D2 receptor activation
Activation of opioid endogenous
system: -opioid receptors
(supraspinal level) and -opioid
receptors (spinal level)

Blockade
Activation
Inverse correlation between increase
in Ca2+ channel density and analgesic
effect; Ca2+-uptake inhibition
Adenosine availability; local release
of adenosine; activation of adenosine
A1 receptor
Central level: inhibits NMDAinduced spinal hyperalgesia
Peripheral level: Potentiated by
NMDA receptor antagonists
GABAB receptor function
Substance-P-induced behavior;
production of substance P
Peripheral modulation
Prostaglandin-E2-like activity
NO release
Migration of macrophages
Production of TNF-

Antidepressant
TCAs, SNRIs, SSRIs
IMAOs
SNRI: venlafaxine
Atypical: trazodone
TCAs: imipramine, nortriptyline, maprotiline
SNRIs: milnacipran
SSRIs: fluoxetine, fluvoxamine
NRIs: nisoxetine
TCAs: imipramine
Atypical: trazodone
NRIs, TCAs, SNRIs
IMAOs
TCAs: amitriptyline, imipramine, dothiepin
SNRIs: milnacipran, venlafaxine
NRIs: reboxetine, (+)-oxaprotiline, ()-oxaprotiline
SSRI: paroxetine
Atypical: mirtazapine
IMAO: moclobemide
TCAs: imipramine, nortriptyline, maprotiline
SNRI: milnacipran
NRI: nisoxetine
TCAs: desipramine, nortriptyline
DNRIs
DNRI: nomifensine
TCAs: amitriptyline, clomipramine, desmethylclomipramine, imipramine,
desipramine, maprotiline, nortriptyline, amoxapine, dothiepin
SNRI: venlafaxine
SSRI: paroxetine
NRIs: (+)-oxaprotiline, viloxazine
DNRI: nomifensine
Atypical: nefazodone, mirtazapine, mianserin
TCAs: amitriptyline, imipramine, trimipramine, desipramine, doxepin
TCAs: amitriptyline, clomipramine
TCAs: amitriptyline, clomipramine, imipramine, trimipramine, desipramine,
doxepin
SSRI: citalopram
NRI: oxaprotiline
TCA: amitriptyline
TCAs: amitriptyline, desipramine
TCAs: clomipramine, desipramine
TCAs: amitriptyline, desipramine
SSRI: fluoxetine
TCAs: imipramine, clomipramine
SSRI: fluoxetine
TCA: amitriptyline
TCAs: amitriptyline, clomipramine
SSRI: fluoxetine
TCA: amitriptyline
SSRI: fluoxetine
TCA: clomipramine
TCA: amitriptyline

Source: Adapted with permission from [58.]

Abbreviations: DNRI, dopamine and norepinephrine reuptake inhibitors; IMAO, monoamine oxidase inhibitor; NO, nitric oxide; NRI,
norepinephrine reuptake inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant; TNF-, tumor
necrosis factor .

estimate the number needed-to-treat (NNT) to obtain a clinically meaningful response in one patient
(such that a lower NNT suggests better efficacy), or
a mean difference between treatment and placebo
across multiple trials using a common continuous

outcome measure [56]. Several obstacles to the interpretation of NNT data and their generalizability to
clinical practice include heterogeneity of trial design
(e.g., specic pain condition and size of population
studied, control groups, parallel vs. crossover design,

228

Ian Gilron

outcome measures), the short-term nature of most

RCTs, and limited consideration for other important outcomes (e.g., disability, quality of life). However, since relatively few trials are available that directly
compare one active treatment to another [85], meta-analysis is currently the most suitable approach to
evaluating a given therapeutic intervention in the context of other available treatment options. Given data
suggesting that pain reductions of as little as 30% are
reported as clinically meaningful by trial patients [21],
more recent meta-analyses have also been using 30%
pain relief as an outcome of relevance, in addition to
the more traditional 50% relief metric.
Several recent meta-analyses (see Tables III, IV)
indicate that antiepileptics [23,59,60,87] and antidepressants [23,49,69] have been studied in multiple high-quality placebo-controlled trials of neuropathic pain.

and bromyalgia) has reported NNTs of 9.6 (95% CI:

7.414) for patient global impression of change (PGIC)
very much improved and 6.1 (4.98.0) for much or
very much improved [60]. Pregabalin, a more recent
congener of the 2 calcium channel ligand, gabapentin
[10], has been studied in several large RCTs conducted
in patients with diabetic neuropathy, postherpetic neuralgia, and central neuropathic pain. A recent metaanalysis reported variable results depending on daily
pregabalin doses ranging from 300 to 600 mg/day (i.e.,
higher doses associated with lower NNTs), with NNTs
of 3.95.3 for postherpetic neuralgia and 511 for diabetic neuropathy [59]. Two central neuropathic pain
RCTs, both involving daily doses of 600 mg, yielded an
NNT estimate of 5.6 [59]. Analgesic interactions between antiepileptics and other drugs in the treatment
of neuropathic pain have been evaluated in several

Table III
Systematic reviews of antiepileptic drugs for pain relief

Antiepileptic Drugs

Condition

Reference

Study Drug (No. Trials)

NNT

Various neuropathic
conditions

[23]

Gabapentin (14)

4.36.4

Pregabalin (14)

3.84.8

Trigeminal neuralgia

[87]

Carbamazepine (2)

1.42.8

Postherpetic neuralgia

[59]c

Pregabalin [300-600 mg] (8)

3.95.3

[60]

Gabapentin (4)

4.37.7

Diabetic neuropathy

[59]

Pregabalin, 300600 mg (17)

511

[60]

Gabapentin (3)

4.728

Central neuropathic pain

[59]

Pregabalin, 600 mg (2)

3.514

Abbreviations and symbols: NNT, number needed-to-treat (relative to placebo);

NNT values (for 50% pain reduction) are lower at higher doses; indicates NNT for
PGIC much or very much improved: NNTs are higher for very much improved
only.
Table IV
Systematic reviews of antidepressant drugs for neuropathic pain

Reports of multiple high-quality neuropathic pain RCTs

are available for carbamazepine/oxcarbazepine, gabapentin, lacosamide, lamotrigine, levetiracetam, pregabalin, topiramate, and valproate [23]. In the setting of
trigeminal neuralgia, meta-analysis of multiple positive RCTs of carbamazepine, and the better-tolerated
oxcarbazepine, resulted in NNT estimates of 1.4 to 2.8
[22,87]. Gabapentin has been evaluated in several RCTs
of patients with diabetic neuropathy, postherpetic neuralgia, and other neuropathic conditions. Previous meta-analyses of gabapentin have yielded NNT estimates
ranging from 4.3 to 6.4 [23,87]. However, it is interesting to note that a more recently updated Cochrane review of gabapentin ecacy (for daily doses of 1,200 mg
or more) across diverse conditions (neuropathic pain

Condition

Ref.

Study Drug (No. Trials)

NNT

Various neuropathic
conditions

[69]

Amitriptyline (10)

2.54.2

Various neuropathic
conditions

[23]

Diabetic neuropathy

[49]

Desipramine (2)

1.94.5

Imipramine (3)

1.73.2

TCAs (23)

1.93.8

SSRIs (4)

3.927

SNRIs (7)

3.414

Duloxetine (3)

510

Abbreviations: NNT, number needed-to-treat (relative to placebo);

SNRIs, serotonin-norepinephrine reuptake inhibitors; SSRIs,
serotonin-selective reuptake inhibitors; TCAs, tricyclic
antidepressants.

combination trials [28]. In two randomized controlled

crossover trials, Gilron and colleagues reported that
combining gabapentin with morphine [27] or with nortriptyline [26] results in superior analgesic ecacy in

Antiepileptics and Antidepressants for Neuropathic Pain

229

comparison with each respective monotherapy. Further support of the ecacy of a gabapentinoid-opioid
combination is suggested by an add-on trial reporting
that oxycodone enhances gabapentin ecacy [34] and
by an open-label study suggesting that an oxycodonepregabalin combination was superior to either drug
alone [24]. A meta-analysis of this small number of
studies suggested superiority of a gabapentinoid-opioid combination over gabapentin alone, but comparison of a gabapentinoid-opioid combination versus an
opioid alone was not possible owing to limitations in
trial designs [12]. Another RCT of a pregabalin-duloxetine combination is discussed below.

demonstrated that combining nortriptyline with gabapentin provided greater reductions in pain and sleep
interference versus either drug alone. More recently, a
large, multicenter double-blind trial [77] evaluated the
combination of pregabalin (300 mg/day) and duloxetine (60 mg/day) in comparison with either high-dose
monotherapy (600 mg/day pregabalin or 120 mg/day
duloxetine) in diabetic neuropathy patients who failed
to respond to monotherapy at lower doses (300 mg/day
pregabalin or 60 mg/day duloxetine). This trial was negative (i.e. no signicant dierence between combination and high-dose monotherapy for the primary pain
outcome); however, all secondary outcome measures
favored combination treatment, and side eects were
generally similar in both groups [77].

Antidepressant Drugs
Results from over a dozen RCTs of tricyclic antidepressants support their ecacy for neuropathic pain conditions including diabetic neuropathy [52], postherpetic
neuralgia [67], and central poststroke pain [46], with recently estimated NNTs of 1.73.2 for imipramine, 1.9
4.5 for desipramine, and 2.54.2 for amitriptyline (see
Table IV). However, it is important to note that highquality RCTs failed to demonstrate ecacy of tricyclic
antidepressants in HIV-related neuropathy [43,72] or in
lumbar radiculopathy [41]. SSRIs have been less extensively studied in neuropathic pain. An estimated NNT
of 6.8 for SSRIs [23] suggests that they are less eective
than TCAs, a result also reported by a head-to-head
comparison of paroxetine versus imipramine [74]. SNRIs such as venlafaxine and duloxetine have been evaluated more recently and were superior to placebo in several RCTs with NNT estimates of 5 to 14 (see Table IV).
Of interest because of its distinct pharmacological actions, the dopamine-norepinephrine reuptake blocker,
bupropion, showed promising results in a single RCT
involving mixed neuropathic pain conditions [70]; however, these results have not since been replicated, and a
subsequent RCT in mostly non-neuropathic low back
pain failed to show a bupropion versus placebo dierence [37]. Analgesic interactions between antidepressants and other drugs in the treatment of neuropathic
pain have been evaluated in several combination trials [12,28]. Gra-Radford et al. [32] observed no benet of combining amitriptyline with the neuroleptic,
uphenazine, in the setting of postherpetic neuralgia,
and Khoromi et. al. [41] reported the lack of ecacy
of nortriptyline, either alone or in combination with
morphine, for the treatment of lumbar radiculopathy.
However, Gilron et al. [26] conducted an RCT that

Prevention of Chronic Neuropathic Pain

Over the past 20 years, increasing attention has been
devoted to studying the potential for analgesic interventions to prevent, or at least suppress, the pathogenesis of chronic pain following acute tissue or
nerve injury, be it surgical, traumatic, or otherwise
[19,31,62,82]. Most recently, the U.S. Food and Drug
Administrationtogether with several other institutionshas established a new private-public partnership (ACTTION: Analgesic Clinical Trial Translations, Innovations, Opportunities, and Networks),
one goal of which is the prevention of chronic pain
[68]. In the setting of surgery, certain procedures may
cause chronic pain; that is, pain persisting beyond 36
months after surgery [40]. Previous studies evaluating patients over time have identied various surgical
procedures that are associated with a high incidence
(proportion of operated patients) of chronic postsurgical pain including, among others, limb amputation
(3050%), breast cancer surgery (2030%), thoracotomy (3040%), and coronary bypass surgery (3050%)
[64]. Other situations where a rather predictable and
discrete insult may lead to the development of chronic
pain include varicella-zoster virus reactivation (shingles) and its occasional progression to postherpetic
neuralgia [19], as well as the administration of cancer chemotherapies that may lead to chemotherapyinduced peripheral neuropathic pain [89]. Given that
well-established chronic pain is often resistant to
therapy, investigative eorts are expanding to identify
and evaluate potentially preventive treatments, including antidepressants and antiepileptics. With continued research occurring in this area, at least one recent

230
systematic review has been recently published, which
includes over three dozen trials of gabapentin/pregabalin, NMDA antagonists, opioids, NSAIDs, and corticosteroids [11].

Antiepileptics for Preventing Chronic

Neuropathic Pain
The potential for gabapentin and pregabalin to prevent and/or treat chronic pain after surgery has
been studied in over a dozen trials that have yielded mixed results to date. In a recent systematic review of multiple, high-quality, chronic postsurgical pain prevention trials by our group, we reported
that available evidence from 15 published RCTs does
not support the efficacy of gabapentin or pregabalin
in the prevention of chronic pain after surgery [11].
In the setting of chemotherapy-induced neuropathy,
one group reported promising results from a small
study on the preventive effects of oxcarbazepine [2],
whereas a different group observed no effect of carbamazepine [81] on the development of oxaliplatininduced neuropathy. Thus, it is premature to draw
conclusions on the potential impact of antiepileptics
on chemotherapy-induced neuropathic pain. In the
setting of varicella-zoster reactivation, a small, openlabel comparison suggested a substantially higher
rate of postherpetic neuralgia in patients treated
with oral carbamazepine versus those receiving oral
prednisolone [39]. Although gabapentin has not been
evaluated for prevention of postherpetic neuralgia,
favorable results from a single-dose study of gabapentin in acute herpes zoster [8] support the feasibility
of conducting such an investigation.

Antidepressants for Preventing Chronic

Neuropathic Pain
In the setting of varicella-zoster reactivation, Bowsher [9] published a double-blind placebo-controlled
trial and reported that 90 days of amitriptyline (25 mg
daily) administration, initiated soon after rash onset,
signicantly reduced the prevalence of postherpetic
neuralgia pain 6 months after onset. However, this
trial has been criticized for the potential confounding
eects of allowing study physicians to decide whether or not study patients were to receive early antiviral
therapy [16]. In the setting of chemotherapy-induced
neuropathy, Kautio et al. [38] observed no signicant
eect of 8 weeks of low-dose (1050 mg/day) amitriptyline treatment when given to patients who had

Ian Gilron
already developed neuropathic symptoms following chemotherapy administration. In our recent Cochrane review of pharmacological interventions for
the prevention of chronic pain after surgery, we only
identied one antidepressant RCT [11]. Results of this
mastectomy trial suggested that 10 days of early postoperative treatment with venlafaxine was associated
with less frequent painful symptoms at 6 months [1].

Pain Treatment Guidelines

Developing and disseminating a clinical guideline or
recommendation is a very complex process involving
the assembly and collaboration of appropriate individuals with prociency in informatics, epidemiology,
biostatistics, health services research, scientic communication, and, of course, clinical expertise in the
area of interest [71]. The process of treatment guideline development starts with careful examination of
available RCT evidence with respect to its validity,
generalizability, and, of course, the evidence of ecacy, tolerability, and other relevant considerations such
as cost-eectiveness. Reviewed evidence may be categorized over a range from Ia (very large high-quality
RCTs and/or meta-analysis of multiple high-quality
RCTs) down to IV (expert opinion), and strength of
recommendations can range from A (based on category I evidence) down to D (based on category IV
evidence) [71]. Furthermore, other treatment-related
factors [20] may be incorporated including treatment
cost, ease of administration, and, in some cases, regulatory and other social issues (e.g., opioids, cannabinoids). Given their complexity and broad-reaching
implications, both the producers and consumers
of treatment guidelines need to be acutely aware of
possible conicts of interest that may aect their development and potentially misguide the best possible
patient care [13].

Pain Treatment Guidelines Regarding

Antiepileptic Drugs
Gabapentin and pregabalin have been recommended
as rst-line therapy for neuropathic pain (with the exception of trigeminal neuralgia) by the European Federation of Neurological Societies (EFNS), the Canadian
Pain Society (CPS), and the IASP Neuropathic Pain
Special Interest Group (NeuPSIG) [3,17,61], and the
EFNS and CPS recommend carbamazepine as rst-line
therapy for trigeminal neuralgia [3,14,61] (see Table V).

Antiepileptics and Antidepressants for Neuropathic Pain

231

Table V
Pain treatment guidelines regarding antiepileptic drugs
Condition

Reference

Drug

Neuropathic
pain

[17]

Gabapentin, pregabalin

First-line

[61]

Gabapentin, pregabalin

First-line

Carbamazepine

First-line (for trigeminal neuralgia only)

Gabapentin, pregabalin

First-line

Carbamazepine

First-line (for trigeminal neuralgia only)

[3]

Pain Treatment Guidelines Regarding

Antidepressant Drugs
In the setting of neuropathic pain (with the exception
of HIV neuropathy), tricyclic antidepressants have been
recommended as rst-line therapy by the EFNS [3],
CPS [61], and NeuPSIG [17] (see Table VI). Whereas
the Canadian and European guidelines recommended
SNRI antidepressants as second-line therapy because
of estimates suggesting somewhat lesser ecacy than
TCAs, the most recent NeuPSIG guidelines consider
them as rst-line, possibly due to a more favorable sideeect prole.
Table VI
Pain treatment guidelines regarding antidepressant drugs
Condition

Reference

Drug

Neuropathic
pain

[17]

Secondary amine
TCAs; SNRIs

[61]
[3]

Treatment
Recommendation
First-line

TCAs

First-line

SNRIs

Second-line

TCAs

First-line

SNRIs

Second-line

Abbreviations: NNT, number needed-to-treat (relative to placebo);

SNRIs, serotonin-norepinephrine reuptake inhibitors; TCAs, tricyclic
antidepressants.

Pharmacokinetics, Safety,
and Dosing
Given the diversity of medications in these two drug
classes and the complexity of their pharmacokinetics,
pharmacodynamics, and drug interactions in dierent
clinical situations [80], prescribers are strongly encouraged to review specic relevant details (especially potential drug-drug interactions) of individual drugs before
prescribing them. Patients with neuropathic pain in particular frequently receive many other medications [80]
and often suer from other coexisting medical problems;
consideration of such comorbidities in the setting of
chronic pain treatment has recently been reviewed [33].

Treatment Recommendation

Antidepressants
Generally, TCAs are well absorbed when taken orally,
with apparent volumes of distribution of up to 10 to
50 L/kg, and most are inactivated and eliminated over
periods of several days [4]. Metabolism of TCAs involves oxidation by hepatic microsomal enzymes and
then conjugation with glucuronic acid [4]. The antidepressants desipramine and nortriptyline are active
metabolites of their parent compounds, imipramine
and amitriptyline, respectively. Liver metabolism of
antidepressant drugs largely involves the cytochrome
P450 family of isoenzymes such that most tricyclics are
substrates for CYP1A2; citalopram and imipramine for
CYP2C19; atomoxetine, duloxetine, mirtazapine, paroxetine, trazodone, and some tricyclics for CYP2D6;
and some tricyclics and SSRIs for CYP3A3/4 [4]. As
well as being substrates, some antidepressants also inhibit the metabolic activity of cytochrome P450 isoenzymes including uvoxamine (inhibits CYP1A2,
CYP2C9, and CYP2C19), uoxetine (CYP2C9 and
CYP2D6), and paroxetine (CYP2D6) [4]. These aspects of antidepressant drug metabolism give rise to
the potential for multiple drug-drug interactions, several of which are highlighted in Table VII [33]. TCAs
may cause several important adverse eects, including
cardiac conduction block, sedation, orthostatic hypotension, confusion, weight gain, and anticholinergic
eects such as dry mouth, constipation, urinary retention, and blurred vision (see Table VIII). The potential
for these complications warrant caution (e.g., electrocardiogram screening) or may even preclude their use
in certain patients including those with recent myocardial infarction, heart block of any degree, prostatic
hypertrophy, narrow angle glaucoma, and others (see
Table VIII). The SNRIs duloxetine and venlafaxine are
generally better tolerated, with fewer and less serious
adverse eects than TCAs (see Table VIII). However,
possible associations between venlafaxine and increased blood pressure [53] contraindicate the use of

Table VII
Interactions and practical recommendations for use of antidepressants and antiepileptics
Tramadol (Prodrug,
Activated by CYP2D6)

Paroxetine (SSRI, Strong

CYP2D6 Inhibitor)

Carbamazepine (CYP3A4
Substrate and Inducer)

Concomitant use may

increase risk of upper GI
tract bleeding; in long-term
concomitant use, monitor
blood cell counts and
consider use of
gastroprotection (e.g.,
proton pump inhibitors)
(B4)

Concomitant use of
tramadol and other
serotonergics may cause
serotonin syndrome; choose
an alternative analgesic that
does not increase serotonin
activity (C1)

Increased plasma levels and

toxicity of amitriptyline; additive
effects on monoamines; if
concomitant use is considered
necessary, monitor plasma
concentrations of TCA and
consider dose reduction;
consider use of an SSRI that does
not inhibit CYP2D6 (e.g.,
citalopram) (C3)

Carbamazepine may reduce

the serum levels of TCAs;
impaired therapeutic response
to TCAs may occur; monitor
therapeutic response and
serum levels of TCAs when
concurrent carbamazepine is
used; consider use of
oxcarbazepine instead of
carbamazepine (C4)

Concomitant use may be associated with increased risk of

bleeding; careful monitoring of signs and symptoms of
acute and/or chronic bleeding is recommended in
concomitant use (B0)

Venlafaxine

Concomitant use of
NSAIDs and SSRIs or
venlafaxine significantly
increases risk of GI
bleeding; if concomitant
use cannot be avoided,
consider use of
gastroprotection with a
proton pump inhibitor (C4)

Concomitant use of
tramadol and other
serotonergic drugs may
cause serotonin syndrome;
choose an alternative
analgesic that does not
increase serotonin activity
(C1)

Increased frequency of
anticholinergic adverse effects
and a few cases of serotonin
syndrome have been reported in
patients treated with both drugs;
avoid combination; if a
combination of an SSRI and
venlafaxine is desired, choose an
SSRI without significant effect
on CYP2D6 activity (e.g.,
citalopram) (D4)

Venlafaxine exposure may be

decreased in some patients;
careful monitoring of
therapeutic response to
venlafaxine is recommended;
therapeutic drug monitoring
can be used to titrate the
venlafaxine dose (B3)

Risk of bleeding may be increased in concomitant use;

signs of increased anticoagulant response and bleeding
(blood hemoglobin concentration) should be carefully
monitored in concomitant use (C0)

Duloxetine

Concomitant use may

increase the risk of upper
GI tract bleeding; in long
term concomitant use,
monitor blood cell counts
and consider use of
gastroprotection (e.g.,
proton pump inhibitors)
(C0)

Concomitant use may

decrease the analgesic effect
of tramadol; concomitant
use of duloxetine and
tramadol may predispose
patients to serotonin
overactivity and serotonin
syndrome; avoid
combination; choose an
analgesic other than
tramadol (D0)

Concomitant use of paroxetine

and duloxetine increases the
plasma concentrations of both
drugs and the risk of
serotonergic and possibly
anticholinergic adverse effects;
avoid combination (D3)

Duloxetine exposure may be

decreased in concomitant use;
monitor therapeutic effect of
duloxetine in concomitant
use; duloxetine dose may need
to be increased (BO)

Duloxetine may impair thrombocyte function and thus

increase risk of bleeding; 1 case report of increased INR
from concomitant treatment; signs of increased
anticoagulant response (INR) and bleeding (blood
hemoglobin concentration) should be monitored in
concomitant use (C2)

Carbamazepine

No interactions were found

with the given substances

Carbamazepine may reduce

and shorten analgesic effect
of tramadol; concurrent
tramadol may lower seizure
threshold; combination
should be avoided when
possible; analgesic response
to tramadol should be
carefully monitored in
concurrent use (C3)

No interactions were found with

the given substances

Not applicable

Carbamazepine reduces anticoagulative response to

warfarin if used concomitantly; over-anticoagulation
may occur in patients stabilized with warfarin and
carbamazepine when carbamazepine use is stopped
without readjustment of warfarin doses; frequent
monitoring of INR is recommended when carbamazepine
is added to or withdrawn from regimen of patient taking
warfarin; dose reduction of about 50% may be needed on
discontinuation of carbamazepine; oxcarbazepine may be
used instead of carbamazepine (C4)

Drug

Ibuprofen (NSAID)

Amitriptyline,
nortriptyline ,
desipramine

Warfarin

Source: [33]. Data from the Swedish-Finnish Interaction X-referencing interaction database.
Abbreviations: CYP, cytochrome P450; GI, gastrointestinal; INR, international normalized ratio; NSAID, nonsteroidal anti-inflammatory drug; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic
antidepressant. Classification: A, minor interaction of no clinical relevance; B, clinical outcome of the interaction is uncertain and/or may vary; C, clinically relevant interaction that can be handled by dose
adjustments, for example; D, clinically relevant interaction that is best avoided. Level of documentation: 0, data derived from extrapolation on the basis of studies with similar drugs; 1, data derived from
incomplete case reports and/or in vitro studies; 3, data derived from studies among healthy volunteers and/or on pilot studies among patients; 4, data derived from controlled studies in relevant patient
population.

Table VIII
Adverse drug reactions, precautions, and contraindications of antidepressants and antiepileptics [33]
Medication

Major Adverse Effects

Precautions

Contraindications

Comments, Recommendations

Cardiac conduction block,

sedation, confusion,
anticholinergic effects (dry
mouth, constipation, urinary
retention, blurred vision),
orthostatic hypotension, weight
gain

Use with caution in patients with history

of seizures, prostatic hypertrophy, urinary
retention, chronic constipation, narrow
angle glaucoma, increased intraocular
pressure, or suicidal ideation; use with
caution in patients receiving concomitant
SSRI, SNRI, or tramadol treatment

Recovery phase after

myocardial infarction,
arrhythmias (particularly heart
block of any degree),
concomitant use of MAO
inhibitors, porphyria

ECG screening recommended in adults >40 y;

heart rate and blood pressure follow-up (both
supine and standing measurements)
recommended with dose escalation; ECG and
blood concentration follow-up recommended
at doses >150 mg/d; follow-up of weight
recommended, especially in diabetic patients

Duloxetine

Nausea, loss of appetite,

constipation, sedation, dry
mouth, hyperhidrosis, anxiety

Use with caution in patients with history

of mania, seizures, or bleeding tendency or
those taking anticoagulants; use with
caution in patients receiving concomitant
SSRI or tramadol treatment

Concomitant use of MAO

inhibitors; uncontrolled
hypertension

Blood pressure follow-up recommended in

patients with known hypertension and/or
other cardiac disease, especially during the
first month of treatment; smokers have almost
50% lower plasma concentrations of
duloxetine compared with nonsmokers

Venlafaxine

Nausea, loss of appetite,

hypertension, sedation,
insomnia, anxiety, dry mouth,
hyperhidrosis, constipation

Use with caution in patients with

hypertension; use with caution in patients
receiving concomitant SSRI or tramadol
treatment

Concomitant use of MAO

inhibitors

Blood pressure follow-up recommended

Gabapentin

Sedation, dizziness, weight gain,

edema, blurred vision

Simple antacids reduce bioavailability

Pregabalin

Sedation, dizziness, weight gain,

edema, blurred vision

Carbamazepine

Somnolence, dizziness,
headache, ataxia, nystagmus,
diplopia, blurred vision, nausea,
rash, hyponatremia, leukopenia,
thrombocytopenia,
hepatotoxicity

Consider risk of pharmacokinetic

interactions with concomitant
medications

Oxcarbazepine

Somnolence, dizziness,
headache, diplopia, nausea,
fatigue, hyponatremia, ataxia

2530% risk of cross-allergy with

carbamazepine

Antidepressants
TCAs
Nortriptyline
and
desipramine
(amitriptyline,
imipramine)

SNRIs

Antiepileptics
Follow-up of weight recommended,
especially in diabetic patients
Follow-up of weight recommended,
especially in diabetic patients
Atrioventricular block,
concomitant use of MAO
inhibitors, porphyria

Liver enzymes, blood cells, platelets, and

sodium levels should be monitored, at least
during the first year; induction of
microsomal enzymes may influence
metabolism of several drugs
Does not entail enzymatic induction; sodium
levels should be controlled during the first
months of treatment

Abbreviations: ECG, electrocardiography; MAO, monoamine oxidase; SNRI, selective noradrenergic reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic
antidepressant.

234

Ian Gilron

SNRIs in patients with uncontrolled hypertension. Serotonin syndrome is a potentially fatal condition associated with several TCAs, SSRIs, SNRIs, and MAOIs, as
well as tramadol and several opioids, and is manifested
as a spectrum of toxicity ranging from agitation to diaphoresis, hyperthermia, myoclonus, tremor, and confusion [76]. Although fatal cases of serotonin syndrome
have been mostly attributed to combinations of MAOIs
with other serotonergic drugs, concerns about serotonin syndrome suggest using extreme caution when
combining any two or more serotonergic agents in the
setting of pain management [33]. Recommendations for
starting dosage, titration, maximum dosage, and duration of adequate individual drug trial are listed in Table
IX for TCAs and the SNRIs duloxetine and venlafaxine.

Antiepileptics
Whereas the oral absorption of pregabalin is quite fast
(approximately 1 hour to maximal absorption), and oral
bioavailability remains dose-independently high [6], absorption of gabapentin is slightly slower (23 hours to
maximal absorption) and occurs through a saturable

transport system in the gastrointestinal tract such that

bioavailability decreases with increasing doses [55].
Therefore, gabapentin dose increases in higher dose
ranges should be expected to lead to incrementally
smaller increases in plasma drug concentrations (i.e.,
nonlinear pharmacokinetics). The lack of hepatic enzyme inhibition or induction and the lack of clinically
important drug interactions are major perceived advantages of gabapentin and pregabalin. However, oral
antacids are known to diminish the bioavailability of gabapentin by 2030% [54]. As with other sedating drugs,
gabapentin and pregabalin can potentiate the eects of
other central nervous system depressants such as ethanol and benzodiazepines. Doses of both drugs should
be reduced proportional to creatinine clearance in the
presence of renal insuciency, since they are normally excreted unchanged in the urine [6,54]. Relatively
frequent adverse eects of gabapentin and pregabalin include sedation, dizziness, weight gain, peripheral
edema, and blurry vision (see Table VIII); these eects
are generally dose-related and reversible. Although carbamazepine is only recommended as rst-line therapy

Table IX
Prescribing recommendations for antiepileptics and antidepressants in neuropathic pain management
Drug

Duration of
Adequate Trial

Starting Dosage

Titration

Maximum Dosage

25 mg at bedtime

Increase by 25 mg daily
every 37 days as
tolerated

150 mg daily; if blood

level of active
medication and its
metabolite is below 100
ng/mL (mg/mL),
continue titration with
caution

68 weeks with
at least 2 weeks
at maximum
tolerated
dosage

Duloxetine

30 mg once daily

Increase to 60 mg once
daily after one week

60 mg twice daily

4 weeks

Venlafaxine

37.5 mg once or twice

daily

Increase by 75 mg each
week

225 mg daily

46 weeks

Gabapentina

100300 mg at bedtime
or 100300 mg three
times daily

Increase by 100300
mg three times daily
every 17 days as
tolerated

3600 mg daily (1200 mg

three times daily);
reduce if renal function
impaired

38 weeks for
titration plus 2
weeks at
maximum
dosage

Pregabalina

50 mg thrice daily or 75
mg twice daily as
tolerated

Increase to 300 mg
daily after 37 days,
then by 150 mg/d every
37 days as tolerated

600 mg daily (200 mg

three times or 300 mg
twice daily); reduce if
renal function impaired

4 weeks

Carbamazepineb

100200 mg daily

Increase weekly by 100200 daily

1600 mg daily

68 weeks

Tricyclic Antidepressants
Secondary amine TCAs:
Nortriptylinea,
desipraminea (use a
tertiary amine TCA
only if a secondary
amine TCA is not
available)
SNRI Antidepressants

Antiepileptics

Abbreviations: SNRIs, serotonin-norepinephrine reuptake inhibitors; TCAs, tricyclic antidepressants.

a
Consider lower starting dosages and slower titration in geriatric patients.
b
Recommended only for treatment of trigeminal neuralgia [18].

Antiepileptics and Antidepressants for Neuropathic Pain

for trigeminal neuralgia, some pharmacological details
are presented here. Bioavailability of carbamazepine is
variable, and its pharmacokinetics also change (reduced
half-life) over the rst few weeks of treatment owing to
auto-induction of CYP3A4-mediated metabolism [44].
Carbamazepine-induced induction is also responsible
for potential drug interactions with various antidepressants, opioids, and other drugs (see Table VII). Toxicities of carbamazepine include adverse eects such as
somnolence, dizziness, headache, ataxia, nystagmus,
diplopia, blurred vision, nausea, rash, hyponatremia,
leukopenia, thrombocytopenia, and hepatotoxicity,
thus necessitating frequent clinical biochemical monitoring (see Table VIII). Recommendations for starting
dosage, titration, maximum dosage, and duration of an
adequate individual drug trial are listed in Table IX for
gabapentin, pregabalin, and carbamazepine.

235
[5]

[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]

[15]

Conclusions
Although initially developed for other conditions, a
wide variety of antidepressant and antiepileptic drugs
have been extensively studied for their ecacy in treating neuropathic pain. According to accumulating evidence, these two classes of agents play an important
role in the clinical management of these conditions.
Continued investigation of currently available as well
as novel antidepressants and antiepileptics is expected
to advance our knowledge about the mechanisms and
management of neuropathic pain.

Acknowledgments
This work was supported, in part, by funding from
CIHR Grant #85649 and Queens University Grant
#383-861 to Dr. Ian Gilron.

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[18]

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Correspondence to: Ian Gilron, MD, MSc, FRCPC, Director,

Clinical Pain Research, Departments of Anesthesiology and
Perioperative Medicine, Queens University, Kingston General
Hospital, 76 Stuart St, Kingston, ON K7L 2V7, Canada. Email:
gilroni@queensu.ca.