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380 Philip Wenn Hsin PENG, Geoff Alexander BELLINGHAM
Recently, duloxetine has proved efficacious for the
treatment of diabetic peripheral neuropathic pain
and is the first medication to be granted Food and
Drug Administration and European Medicines
Agency approval for management of this pain
syndrome [27, 32, 87, 89, 93, 98].
Mechanisms of action
Antidepressant medications can produce analgesic
effects through a number of mechanisms. In the
past, the primary mechanism was believed to involve
modulation of the descending inhibitory pain
pathway through serotonin and norepinephrine
re-uptake inhibition [53, 61]. However, further
research has elucidated several other mechanisms
of action.
Serotonin and norepinephrine re-uptake
inhibition
e serotonergic and noradrenergic systems in
the central nervous system have been identified as
important mediators of the descending inhibitory
control of nociceptive input [6, 88]. A dysfunction
in this system can lead to heightened sensitivity
to pain as well as painful responses to normally
non-painful stimuli. Studies which destroy
serotonin rich structures in the central nervous
system involved in descending inhibition (for
example, the nucleus raphe magnus) or inhibit
serotonin synthesis demonstrate increased primary
hyperalgesia in animal models [6, 88, 104]. e
role of norepinephrine in mediating analgesia has
also been demonstrated in experiments which
inhibit or augment its effects in the central nervous
system [64, 65, 73].
Antidepressants with preferential activity for either
serotonergic or noradrenergic systems can produce
analgesia. However, animal and clinical experiments
have shown that dual acting antidepressants
which effect both systems concurrently are far
more effective at producing pain relief [30, 41,
46, 52, 56, 85]. Such findings may explain why
antidepressants such as SSRIs are not as effective
for treating pain compared with TCAs or SNRIs
since only serotonin levels are affected.
Sodium and calcium channel blockade
Tricyclic antidepressants can block both sodium and
calcium channels, both of which are important in
nociceptive signalling. Indeed, local and peripheral
administration of antidepressants suggests that
they are more potent and longer-acting than
bupivacaine, a long-acting local anaesthetic [33,
44]. Calcium channel blockade may result in
inhibition of presynaptic transmitter release and
postsynaptic impulse generation [81].
NMDA receptors antagonism
Amitriptyline and other TCAs have shown
high-affinity binding to N-methyl-D-aspartate
(NMDA) receptors, and function as NMDA
antagonists at concentrations similar to those
inhibiting monoamine re-uptake [14]. e NMDA
antagonism results in a reduction of neuronal
hyperexcitiability at the spinal cord level unrelated
to the monoamine uptake inhibition [24]. us
NMDA receptor activity plays an important
role in central sensitisation, which contributes to
inflammatory and neuropathic pain.
Opioid action
An interesting observation in the animal model
demonstrated that the acute analgesic effect
from antidepressants could be partially reversed
by naloxone, an opioid antagonist [8]. Chronic
administration of antidepressants was also shown
to alter endogenous opioid levels and binding
in the central nervous system [26]. e affinity
of antidepressants for the mu-opioid receptors,
however, is far too low to be clinically significant
and the opioid connection may be through other
types of receptors [50, 81].
Miscellaneous postsynaptic blockade
A number of postsynaptic receptor blocking
activities of TCAs have been well known for
years and contribute to their major side-effect
profile. ese include H1-histaminergic, alpha-
adrenergic and anticholinergic receptors. However,
those blockade activities may also contribute to
the analgesic effects because each is involved in
nociceptive signalling [75].
Unlike the traditional TCAs, both SSRIs and
SNRIs exhibit minimal activity on muscarinic,
histaminergic and adrenergic receptors and are
probably devoid of action on ion channels (Table
23.01). e improved side-effect profile and
comparable antidepressant effects prompted the use
of both SSRIs and SNRIs as the first-line treatment
of depression.
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Antidepressants and Anticonvulsants 381
Indications
e principal analgesic indication of antidepressants
is the treatment of neuropathic pain. Other
indications include treatment of headache (chronic
tension or migraine) and various myofascial pain
syndromes.
Pharmaceutical preparations
Commonly prescribed drugs of the TCA, SSRI and
SNRI groups, and the dose range for analgesia as
well as basic pharmacology are presented in Table
23.01.
Side eects
e primary problem in using TCAs is related to
their side-effect profile, attributed mainly to the
postsynaptic receptor blocking effects. ese include
anticholinergic effects (dry mouth, constipation,
micturition difficulties), antihistamine effects
(sedation), alpha-adrenergic blockade (orthostatic
hypotension) and sodium/calcium channel
blockade (cardiac conduction abnormalities).
Tricyclic antidepressants must be used with caution
in patients with a history of cardiovascular disease,
glaucoma, urinary retention and autonomic
neuropathy. ey must be administered with
extreme caution in elderly patients [22]. In one
study, 18% of depressed patients with a history
of documented ischaemic heart disease developed
adverse cardiac events with TCAs [67]. us, an
expert panel at a recent international conference
on mechanisms and treatment of neuropathic
pain recommended a screening electrocardiogram
to check for cardiac conduction abnormalities
before beginning treatment with TCAs, especially
in patients older than 40 years old [22]. Also,
TCAs are contraindicated in patients with cardiac
conduction disturbance, within 6 months of
myocardial infarct, and patients with convulsive
disorders. In the latter group, TCAs increase the
tendency to seizure. Narrow angle glaucoma may
be precipitated because of the anticholinergic effect,
but TCAs can be used in patients with adequately
treated glaucoma [81]. In patients at risk of suicide
and overdose, TCAs can be lethal while SSRIs
are relatively safe in overdose [1]. Weight gain is
another potential problem associated with TCAs.
In general, nortriptyline and desipramine are better
tolerated than amitriptyline with fewer side effects
such as dry mouth, constipation and sedation.
In comparison, SSRIs and SNRIs are better tolerated
than the TCAs with minimal anticholinergic,
histaminergic and adrenergic side effects. However,
they are not devoid of side effects. e most
Table 23.01 Dose range for analgesia and basic pharmacology of commonly prescribed antidepressants for
chronic pain syndromes
Drugs Recommended
range for
analgesia (mg
per day)
Re-uptake
inhibition —
norepinephrine
Re-uptake
inhibition
— serotonin
Receptor blockade
α-Ad H1 -
histamine
Muscarinic NMDA
Amitriptyline 10–150 +* + + + + +
Imipramine 10–150 +* + + + + +
Nortriptyline 10–100 ++ (+) + + + +
Desipramine 10–150 ++ (+) + + + +
Venlafaxine 37.5–225 + ++ - - - ?
Duloxetine 60–120 + ++ - - - ?
Paroxetine 20–40 - + - - - ?
Fluoxetine 20–40 - + - - - ?
Data modified from references [28, 36, 49, 81, 105]; * mainly through metabolites nortriptyline, desipramine; () = weak
action;
α-Ad = alpha-adrenergic.
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382 Philip Wenn Hsin PENG, Geoff Alexander BELLINGHAM
common adverse effects are nausea, dyspepsia
(SSRIs), somnolence (SNRIs) and insomnia
(SSRIs). A meta-analysis comparing the side effects
between TCAs and SSRIs showed a decreased
incidence of dry mouth (29%), constipation (11%)
and dizziness (9%) but an increase in risk of nausea
(10%), diarrhoea (8%) and anorexia (5%) with
SSRIs [96].
Ecacy
Neuropathic pain
To estimate the relative efficacy of analgesic agents
in RCTs, the number needed to treat (NNT) is
often used. It is the number of patients that need
to be treated with the drug to obtain one patient
with at least 50% pain relief. e NNT is used to
estimate treatment efficacy, recognising that there
are limitations to this methodology including
variability in randomised controlled trials (e.g.
crossover versus parallel design) and the short-term
nature of most of these trials.
Tricyclic antidepressants are well established for
the treatment of neuropathic pain. Two systematic
reviews of antidepressants in neuropathic pain
revealed a total of 17 randomised controlled trials
involving 10 antidepressants [55, 86]. e NNT
was approximately 2.5. ere was no difference in
the NNT between TCAs with balanced inhibition
of re-uptake of serotonin and norepinephrine
(amitriptyline, imipramine) and those with
relatively selective inhibition of norepinephrine
uptake (desipramine, nortriptyline). Similarly, in
terms of the NNT, the efficacy for TCAs was nearly
identical regardless of the underlying condition
— diabetes mellitus, herpes zoster, traumatic nerve
injury or stroke [28].
Both SNRIs, venlafaxine and duloxetine, have
an NNT of about 4.6 and 5.2 respectively [5].
Venlafaxine has shown efficacy in trials involving
painful diabetic neuropathy [43, 69] and mixed
painful polyneuropathy [82] at dosages of 150–225
mg per day. In the trial by Rowbotham et al. [69], the
NNT was 4.5 at week 6 and was comparable with
those of TCAs and gabapentin. However, in the trial
by Sindrup et al. [82], when venlafaxine was compared
with imipramine, it was not superior to imipramine
with respect to tolerability but imipramine showed a
high proportion of responders.
e efficacy of duloxetine in treating neuropathic
pain has been evaluated in three randomised
controlled trials for patients suffering from painful
diabetic peripheral neuropathy [38, 62, 105]. ere
have been no other randomised controlled trials
evaluating its use for other types of neuropathic
pain syndromes. e primary outcome measure
for these trials was the change in the weekly mean
of the 24-hour average pain scores. All trials
showed statistically significant analgesia and the
effect was maintained throughout the 12-week
trial periods. Duloxetine showed significant
responses at 60 mg daily, but analgesia was not
statistically improved when the dose was increased
to 60 mg twice daily.
e role of SSRIs in the management of neuropathic
pain is unclear. Fluoxetine was not superior
to placebo [52] but two smaller studies found
citalopram and paroxetine [83, 84] efficacious in
the management of painful diabetic neuropathy
independent of their antidepressant effects.
However, the combined NNT for all three studies
was 6.7, indicating that SSRIs do not appear to be
as efficacious as TCAs or SNRIs [85].
In the consensus guidelines published by the
Canadian Pain Society and European Federation
of Neurological Societies (EFNS), both consider
TCAs as the first-line treatment for neuropathic
pain while SNRIs are seen as second line [5, 57]. In
patients with cardiovascular risk factors, the EFNS
even recommend SNRIs over TCAs. e SSRIs
are only considered as the last line of treatment
in both guidelines. e International Association
for the Study of Pain (IASP) has published
guidelines with similar recommendations but with
some variations [23]. e SNRI antidepressants
(venlafaxine and duloxetine) are ranked among
the first-line treatment options for neuropathic
pain alongside TCA antidepressants. e IASP
statement gives preference to secondary amine
TCAs (nortriptyline and desipramine) over tertiary
amine TCAs (amitriptyline and imipramine).
Secondary amine TCAs are better tolerated with
less risk of adverse consequences such as sedation,
anticholinergic effects, or orthostatic hypotension.
Other antidepressants which can be used are
SSRIs (citalopram and paroxetine) and bupropion
(norepinephrine and dopamine re-uptake
inhibitors). However, these are recommended as
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Antidepressants and Anticonvulsants 383
third-line agents if patients fail to respond to an
adequate trial of a TCA or SNRI medication.
e recommended doses for the treatment of
neuropathic pain are shown in Table 23.01.
Headache
e tricyclic antidepressant amitriptyline is the
most widely used drug in the preventive treatment
of tension-type headache and is considered the
drug of choice for this indication [51]. A systematic
review found a superior analgesia over placebo in
15 out of 18 placebo controlled trials [30]. e
recommended daily dose is 10–75 mg. e efficacy
of the SSRIs in chronic tension-type headache
prevention is not well established. Of the 10
controlled trials, three found SSRIs to be no better
and two found them to be marginally superior to
placebo. e remainder of the five trials showed
some improvement but the analgesic effect was not
superior to the comparison drugs [42].
Recent trials evaluating SNRI medications for the
prophylaxis or treatment of headache have included
the use of venlafaxine and duloxetine.
In a randomised, placebo controlled trial for the
prophylactic treatment of patients with tension-
type headache [108], Venlafaxine XR 150 mg/day
for 12 weeks resulted in a significant decrease in
the number of days with headache compared to
placebo with a NNT of 3.5.
Duloxetine has been evaluated for the treatment
of headache in an open label trial which included
chronic migraine and chronic tension-type
headache [101]. is study revealed significant
improvements in pain and depression, which were
evident within the first week of treatment with
duloxetine. A separate study evaluated duloxetine
for migraine prevention in a retrospective chart
review and showed significant but modest results.
Headache frequency decreased from 19.4 to 15.7
per month (p=0.01) [90].
Fibromyalgia
e hypothesised role of serotonin (5-HT)
deficiency in the pathogenesis of fibromyalgia
suggests that increasing synaptic 5-HT by inhibiting
its re-uptake using SSRIs should be beneficial.
However, clinical trials of SSRIs for fibromyalgia
are not encouraging [37]. In contrast, all controlled
trials on TCAs reported a positive treatment effect
[30]. e inferiority of SSRIs to TCAs suggests that
norepinephrine also modulates pain in fibromyalgia
[71, 77, 106].
e SNRI activity of duloxetine has been
evaluated for the treatment of fibromyalgia in three
randomised, placebo controlled trials [2, 3, 70].
All three trials showed significant improvements
in the primary outcome measures, which included
the Fibromyalgia Impact Questionnaire (FIQ)
total score and pain score, Brief Pain Inventory
(BPI) average severity score, and the Patient
Global Impressions of Improvement (PGI-I) score
during the study periods when compared with
placebo. e only score which did not maintain a
significant difference from placebo at the end of the
trial period was the FIQ-pain score in the study
conducted by Arnold et al. [2]. Duloxetine doses
which produced significant differences were 60 mg
given daily and twice daily. In 2008, the United
States Food and Drug Administration approved the
use of duloxetine for the treatment of fibromyalgia
[99].
Low back pain
Early systematic reviews did not support the use
of antidepressants in chronic low back pain [97].
Recently meta-analyses, however, support a positive
effect [74]. In nine randomised controlled trials
with 10 treatment arms, the antidepressant group
showed a small improvement in pain intensity
(0.41, 95% confidence interval 0.22–0.61). Seven
of those trials recruited patients with depression.
Selective serotonin re-uptake inhibitors were
the agents examined in two trials, which showed
conflicting results [4, 19]. However, no studies
examined the effect of antidepressant for more than
2 months. e activities of daily living were not
improved and the patients in the antidepressant
groups experienced more adverse effects than those
in the placebo groups. In view of theses findings,
the antidepressants should be assigned a role as an
adjunct rather than a primary agent.
Clinical application
Please see the section on clinical application of
anticonvulsants.
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384 Philip Wenn Hsin PENG, Geoff Alexander BELLINGHAM
Anticonvulsants
Introduction
Anticonvulsants are considered for alleviation
of neuropathic pain because of their ability
to reduce neuronal excitability. In the United
States, neurologists reported that 45% of their
anticonvulsant prescriptions were for conditions
other than epilepsy, mostly for migraine and
neuropathic pain. Among primary care physicians,
prescriptions of anticonvulsants for non-epilepsy
conditions were even higher (63%) [66].
Problems with the early generation of
anticonvulsants are related to their side-effect profiles
(carbamazepine, phenytoin and sodium valproate).
Newer anticonvulsants (gabapentin, pregabalin,
topiramate, lamotrigine and oxcarbazepine) are
better tolerated.
Brief history
In 1853, Alfred Trousseau from Paris hypothesised
that painful paroxysms seen in trigeminal neuralgia
were due to discharges in the trigeminal system
which were similar to the neuronal discharges
seen in epilepsy. In 1942, Bergouignan tested this
hypothesis by successfully using phenytoin to treat
trigeminal neuralgia [7]. Later, when carbamazepine
was introduced, the treatment efficacy in trigeminal
neuralgia was examined in a placebo controlled
double-blind study, which was among the first
of its kind in pain medicine [15]. Subsequently,
various anticonvulsants have been examined in
different neuropathic pain models such as diabetic
peripheral neuropathy and postherpetic neuralgia.
Mechanisms of action
e mechanisms of various commonly used
anticonvulsants in the management of neuropathic
pain are summarised in Table 23.02.
Carbamazepine, oxcarbazepine and
phenytoin
All three of these anticonvulsants inhibit voltage-
dependent sodium channels. By selectively
blocking the high-frequency action-potential
firing neurons, these sodium channel blocking
agents offer protective activity against seizures. In
acute pain, phenytoin and carbamazepine, when
locally administered, have antinociceptive activity
that is substantially more potent than that of
the sodium channel-blocking local anaesthetic,
lidocaine [95]. Oxcarbazepine is a ketoanalogue
of carbamazepine, essentially 100% absorbed and
converted almost immediately to the active 10-
hydroxyl metabolite, 10,11-dihydro-10-hydroxyl-
5H-dibenzo(b,f)azepine-5-carboxamide. Both
oxcarbazepine and its metabolites inhibit voltage-
dependent sodium channels, while the metabolites
also inhibit potassium channels [39].
Gabapentin and pregabalin
Gabapentin was originally developed as a structural
analogue of gamma-aminobutyric acid (GABA).
Table 23.02 Mechanism of various anticonvulsants for neuropathic pain management
Drugs
Recommended
range for
analgesia (mg
per day)
Sodium
channel
blockade
Calcium
channel
blockade
Glutaminergic
blockade
GABAergic
Carbamazepine 200–1200 + - - -
Oxcarbazepine 600–1800 + - - -
Gabapentin 900–3600 - + - -
Pregabalin 150–600 - + - -
Lamotrigine 100–400 + + - -
Topiramate 50–200 ++++
GABA = gamma-aminobutyric acid.
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Antidepressants and Anticonvulsants 385
Although both gabapentin and pregabalin are
structural analogues of GABA, both have no
direct GABAergic action, and do not block GABA
uptake or metabolism despite their names [31, 92].
e alpha-2-delta subunit of spinal N-type Ca2+
channels is most likely the target of analgesic action
of gabapentin and pregabalin. ey bind to these
presynaptic channels in the dorsal horn, resulting in a
decrease in the release of excitatory neurotransmitters
such as glutamate and substance P [91].
Topiramate and lamotrigine
Topiramate has multiple modes of action, including
modulation of voltage-gated sodium and calcium
channels, potentiation of GABAergic inhibition at
a novel site on the GABAA receptor, and blockade
at alpha-amino-3-hydroxy-5-methylisoxazole-4-
propionic acid (AMPA) and kainate glutamaine
receptors [59]. Lamotrigine is a phenyltriazine
derivative, with a mechanism of action that is
mediated through inhibition of voltage-activated
sodium channels and possibly calcium channels,
so that it prevents the release of excitatory amino
acids, particularly glutamate [47].
Indications
Most of the anticonvulsants are considered for
treatment of neuropathic pain and the choice
is dependent on the analgesic efficacy and side-
effect profile. In addition, some anticonvulsants
are used for migraine therapy. Valproate is the first
anticonvulsant currently approved in the United
States for migraine therapy. Recent controlled
trials have shown that topiramate also reduces
the frequency of migraine attacks, leading to the
approval of the Food and Drugs Administration
in the US for migraine prophylaxis [79]. Several
other anticonvulsants, such as gabapentin and
lamotrigine, seem to be promising for this
indication [66].
Pharmaceutical preparations
Common preparations and recommended daily
doses for the treatment of neuropathic pain and
migraine are listed in Table 23.02.
Side eects
Gabapentin and pregabalin
Both gabapentin and pregabalin are well tolerated,
safe and lack drug interaction as both are excreted
predominantly unchanged through the kidney [31,
68]. e commonest side effects of gabapentin and
pregabalin are dizziness, somnolence, dry mouth
and peripheral oedema, most of which occur in
the initiation phase and are dose related [5, 22, 31,
50, 68]. In the elderly, both drugs can exacerbate
gait imbalance and cognitive impairment. All these
require dosage adjustment and monitoring but
not usually discontinuation of the drug [22]. In
patients with renal insufficiency, the dosage should
be reduced.
Carbamazepine and oxcarbazepine
Commonly reported adverse effects of
carbamazepine are tiredness, headache, dizziness,
nausea and ataxia, which are less frequently seen
in patients treated with oxcarbazepine [72]. Both
drugs are frequently associated with the occurrence
of asymptomatic hyponatraemia, which is rarely
a cause for discontinuation of the medication
[11, 60]. Carbamazepine causes allergic skin
rash, which is less frequent in patients treated
with oxcarbazepine. Slow dosage titration may
reduce the risk. Reversible, mild leucopenia often
occurs with carbamazepine, but does not require
discontinuation of therapy unless accompanied by
evidence of infection or if the white cell count slips
below 1x10
9
.L
-1
[72]. Aplastic anemia and toxic
hepatitis are rarer problems and can be avoided by
replacement with oxcarbazepine [40].
Lamotrigine and topiramate
Lamotrigine is very well tolerated in general.
Adverse effects commonly reported are dizziness,
somnolence, nausea, fatigue and headache (8–20%)
[72]. Rashes develop in about 12% of patients and
typically within the first 8 weeks of lamotrigine
administration, accounting for most frequent
reasons for withdrawal of lamotrigine [58]. Rarely,
severe cutaneous reactions, including Stevens-
Johnson syndrome and toxic epidermal necrolysis,
have been described. e risk of allergic reaction
is correlated to the initial plasma concentration of
lamotrigine. Low starting dose and slow titration
should therefore always be used [76].
Adverse effects from topiramate treatment are
mainly related to cognitive impairment, which
includes dizziness, difficulty with concentration
and speech, somnolence, ataxia, and fatigue [72].
Word finding difficulty seems to be a fairly specific
problem with topiramate and is reported as an
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386 Philip Wenn Hsin PENG, Geoff Alexander BELLINGHAM
adverse effect in up to one-third of patients [16, 78].
e adverse events can be minimised by “starting
low and going slow”. Specific adverse effects are
probably related to the carbonic anhydrase activity
of topiramate and include acroparaesthesia and an
increased risk of developing renal stones. e latter
is related to the increased pH of the urine. e
incidence of nephrolithiasis while on topiramate
treatment is 1.5%, which is two to four times
the incidence expected in the general population
[102]. e paraesthesia seems to decrease with time
or dosage reduction.
Ecacy
Neuropathic pain
At least 13 randomised controlled trials have
been conducted on gabapentin (8 studies) and
pregabalin (5 studies) supporting the analgesic
effects over placebo in various neuropathic pain
syndromes [28, 50]. e NNT for both in the
management of neuropathic pain is approximately
4 [28]. In addition to the NNT, the other factor
to consider in treatment is the effect on quality
of life, sleep and comorbidities. Pregabalin and
gabapentin have been reported repeatedly to have a
significant impact on several measures of quality of
life including sleep. is is in contrast to opioids,
which have not shown significant effects on most
measures of quality of life and mood in randomised
controlled trials [5].
e NNT for carbamazepine and phenytoin is
approximately 2.1–2.3 for diabetic peripheral
neuropathy [28]. However, because of the poor
design of those trials and significant adverse
effects of the mediations, both are considered
as poor candidates for first-line therapy [36].
Carbamazepine, however, is still considered first-
line therapy for trigeminal neuralgia, with an
NNT of 1.7 [28, 36, 57]. e analgesic efficacy of
oxcarbazepine for neuropathic pain is comparable
to that of carbamazepine [39]. However, only one
randomised controlled trial (in diabetic peripheral
neuropathy) has been published to date [20].
Lamotrigine has been found to be useful in the
management of trigeminal neuralgia [48, 107],
painful diabetic neuropathy [25], central post-stroke
pain [100] and incomplete spinal cord injury pain
[29]. However, lamotrigine was not found to be
useful in the management of a variety of peripheral
neuropathic pain states [54]. Topiramate has
produced mixed results in various neuropathic trials
including trigeminal neuralgia [35], diabetic painful
neuropathy [63, 94] and chronic lumbar radicular
pain [45]. e beneficial effect was also associated
with common adverse effects in those trials.
Other chronic pain syndromes
Topiramate has been examined in several
randomised controlled trials in the prophylactic
Figure 23.01 Suggested algorithm for pharmacological management of neuropathic pain
*Topical lidocaine refers to Lidoderm® (Endo Pharmaceuticals Inc., Pennsylvania, US) or pharmacy-prepared cream containing
5–10% lidocaine; TCAs = tricyclic antidepressants; CR = controlled release; SNRIs = serotonin norepinephrine re-uptake
inhibitors; third line agents = lamotrigine, topiramate, cannabinoids and selective serotonin re-uptake inhibitors.
First Line Agents
TCAs Gabapentin or Pregabalin *Topical Lidocaine SNRIs
Second Line Agents
CR Opioids
Tramadol
Third Line Agents
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Antidepressants and Anticonvulsants 387
treatment of migraine [50, 79]. A dose of 100 mg
per day appears to lead to only a modest reduction
in mean frequency of migraines experienced per
month. Several other anticonvulsants, such as
gabapentin and lamotrigine, seem to be promising
for this indication [66].
Certain anticonvulsants have been investigated in
the management of other chronic pain syndromes
such as pregabalin in fibromyaglia [17] and
topiramate in chronic low back pain [58]. Early
experience is promising but more studies are
required.
Clinical applications
Both the antidepressants and anticonvulsants play
an important role in the management of neuropathic
pain and migraine prophylaxis. Recently, three
consensus guidelines for the management of
neuropathic pain have been published by the
Canadian Pain Society, European Federation of
Neurological Societies and IASP Neuropathic Pain
Special Interest Group [5, 23, 57]. A treatment
algorithm based on these three guidelines is shown
in Fig. 23.01.
Tricyclic antidepressants are chosen as first-line
agents because of the robust data supporting their
efficacy and the affordable cost [5, 28, 36]. ose
TCAs with sedative qualities (e.g. amitriptyline)
are generally indicated for patients with poor sleep
and if patients find these agents too sedating, a
less sedating agent such as nortriptyline is chosen.
e usual starting dose is 10–25 mg given at
bedtime. e dose may then be titrated every 5 to
7 days until a therapeutic response is achieved or
persistent, bothersome side effects occur [22, 50].
“Start low and go slow” is the key especially when
tricyclic antidepressants are used in elderly patients.
It is unlikely that patients can obtain further
therapeutic benefit beyond a dose of 150 mg/day.
e problem associated with TCAs is the side-effect
profile which makes their use contraindicated in
patients with conditions such as cardiac conduction
abnormalities and prostatic hypertrophy.
Duloxetine, supplied in 30 mg and 60 mg delayed-
release capsules, can be started at either dose, but
the side-effect profile may be lessened by starting at
30 mg daily for 1 week and then titrating up. ere
has been no evidence that exceeding a dose of 60
mg daily confers any additional analgesic benefits
in clinical trials. e analgesic effect of duloxetine is
rapid, which is likely due to its potent and balanced
SNRI activity. Unlike venlafaxine, the activity on
norepinephrine and serotonin pathways is not
dose dependent [12, 13]. Clinical trials evaluating
duloxetine commonly show significant differences
in pain relief compared with placebo within the
first week of treatment.
e common side effects are nausea (20%), dry
mouth (15%), constipation (11%) and insomnia
(11%) [13]. Nausea is a common reason for
patients to discontinue use of the drug, but it tends
to appear early in treatment and subsides quickly,
with the median duration being 7 days [13]. When
taken with food, the severity of nausea will decrease
and the drug may be better tolerated [21].
Gabapentin and pregabalin are also considered as
first-line agents for neuropathic pain management
because they are well tolerated, devoid of major drug
interactions through liver metabolism and associated
with improvement in quality of life including sleep
[5]. Gabapentin is generally started at 300 mg per
day (either as 300 mg once at bedtime or 100 mg
thrice a day) and gradually increased every 3 to 5
days. e target dose is 1800 to 3600 mg per day.
If only partial pain relief occurs at a dose of 1800
mg per day, titration can be continued up to 3600
mg per day in three to four divided doses [22]. is
slow titration minimises the common side effects of
sedation and dizziness. e recommended starting
dose for pregabalin is 75 mg twice a day and it can
be titrated to 150 mg thrice a day. A daily dose
of 600 mg does not add much therapeutic benefit
and can increase the risk of side effects. However,
post-marketing experience suggests an even lower
starting dose be initiated, especially in the elderly
or patients receiving concomitant administration
of a large dose of opioids or sedating agents such as
benzodiazepines or tricyclic antidepressants.
In the presence of contraindications to tricyclic
antidepressants, pregabalin, gabapentin and even
SNRIs are alternatives. If a certain drug achieves
only a partial response, it is reasonable to consider
adding another agent to improve the analgesic
efficacy and to minimise the side effects [36].
ere is some evidence to support combination
therapy. When morphine is added to gabapentin,
the combination therapy is superior to treatment
with either drug alone [34]. In a study involving
11 patients who did not respond to gabapentin, a
gabapentin-venlafaxine combination was superior
to gabapentin alone [80].
https://t.me/medicina_free
388 Philip Wenn Hsin PENG, Geoff Alexander BELLINGHAM
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