BJA Education, 18(9): 277e283 (2018)

doi: 10.1016/j.bjae.2018.06.002
Advance Access Publication Date: 30 July 2018

Matrix codes: 1A02,

2E03, 3E00

Treatments for neuropathic pain: up-to-date

evidence and recommendations
B.C. Fitzmaurice and A.T.A. Rayen*
Sandwell and West Birmingham NHS Trust, Birmingham, UK
*Corresponding author: [email protected]

Learning objectives Key points

By reading this article, you should be able to: ! Neuropathic pain is often poorly managed, and
! Recognise neuropathic pain and initiate only 33e50% patients benefit from first-line
treatment. analgesics.
! Describe the National Institute for Health and ! Treatment should be based on the updated rec-
Care Excellence (NICE) recommendations on ommendations by NICE and other expert groups.
pharmacotherapy for neuropathic pain. ! Combination therapies are beneficial compared
! Recognise future development in treatment of with monotherapy.
neuropathic pain. ! Pain phenotyping may allow for more stratified
and personalised therapies.

Neuropathic pain (NeP) affects 6e10% adults worldwide. It

hyperalgesia, and dysaesthesia.4 Despite its multitude of
represents an even greater burden than non-neuropathic
causes, a general unified pharmacological approach is
chronic pain, significantly impacting on patients’ lives and
advised to manage NeP. We describe the recommended
with wider socio-economic consequences.1,2
pharmacological approach to manage NeP and some novel
The International Association for the Study of Pain (IASP)
invasive procedures that are reserved for those with re-
defines NeP as ’pain caused by a lesion or disease of the
fractory NeP. Generally, medical treatment is coupled with
somatosensory nervous system’. It is divided into central or
psychological input to produce the holistic approach to
peripheral NeP according to the site of the lesion.3 NeP en-
therapy that these patients require.
compasses a range of clinical conditions: from peripheral
The treatment of NeP is challenging and inadequate for a
NeP conditions such as peripheral diabetic neuropathy (PDN)
variety of reasons. These include diagnostic difficulties and
to central NeP conditions, for example, central post-stroke
insufficient knowledge about available treatment options.
pain. Regardless of the underlying aetiology, NeP is now
Important and commonly prescribed drugs may be unlicensed
regarded as a distinct clinical condition; patients
for these indications.3 Furthermore, available medications
present with similar hallmark characteristics: allodynia,
have limited effectiveness, adverse effects, and abuse poten-
tial.1,4 Outside the specialist setting there remains consider-
able variation in the correct sequencing of therapeutic classes,
Bethany Fitzmaurice FRCA is specialty registrar in anaesthesia in initiation of treatment, and achieving therapeutic dosing.
West Midlands Deanery, with an interest in chronic pain manage- National essential medicines lists (NEMLs) are the lists of
ment. She has published and presented on chronic pain subjects. medicines deemed necessary by the WHO to meet priority
health needs. Analysis of 112 NEMLs shows great deficiencies
Arasu Rayen DA (Ind), DA (UK), FRCA, FFPMRCA, MSc (Pain
in the scope of neuropathic agents.2 Therefore, drugs with
Management), PG Cert Med Ed, FHEA, is a consultant in pain
better efficacy/safety profile and which act on novel targets
management at Sandwell and West Birmingham NHS Trust who
are needed.5
has published and presented in national and international meetings
on chronic pain subjects. He is a former editor of Pain News, the
official newsletter of British Pain Society.

Accepted: 26 June 2018

© 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.
For Permissions, please email: [email protected]

277
Treatments for neuropathic pain

Recommendations and guidelines (iv) High concentration capsaicin patches (8%) are, for the
first time, considered in the recommendations for NeP.
Over the past decade, there have been only a few recom-
mendations in this subject area despite new pharmacother-
apies and several good quality clinical trials. Reasons for this
Novel therapeutic agents
are multifactorial including lack of consistency in methods
used to assess the quality of evidence. Tapentadol
Tapentadol is a single molecule agent with dual actions: mu-
opioid receptor agonism and selective norepinephrine reup-
2017 National Institute for Health and Care Excellence
take inhibition. Tapentadol has a better adverse effect profile
guidelines for the non-specialist setting
including good gastrointestinal (GI) tolerability, improved
The current National Institute for Health and Care Excellence treatment adherence, and lower tolerance and abuse poten-
(NICE) guidelines are based on both clinical evidence and cost- tial compared with older opioids.1,6 Metabolism is by hepatic
effectiveness after a meta-analysis of 115 studies (18,087 pa- glucuronidation, meaning a lower risk of adverse interactions
tients) (see Table 1). NICE recommends providing an individ- with other drugs metabolised by CYP450 enzymes.1
ualised treatment plan with regular reviews.3 In one study with patients with severe chronic neuropathic
low back pain, monotherapy with tapentadol was as effective
as combination therapy with pregabalin.6 The incidence of
NICE guidance
dizziness and somnolence was clinically and statistically
(i) First-line for all NeP, except trigeminal neuralgia (TGN): significantly lower in the group receiving tapentadol alone.
(a) Choice of amitriptyline, duloxetine, gabapentin, or These findings suggest a role for tapentadol as a single agent
pregabalin as initial treatment. in this difficult-to-treat group of patients.
(ii) Second-line:
(a) If initial treatment with a first-line agent is ineffective
or not tolerated, offer one of the remaining three first Cannabinoids
line drugs. Trial all four first-line agents if needed. Cannabinoid receptors, CB1 and CB2, have been linked to pain
(iii) Tramadol should only be considered if acute rescue modulation, with receptor activation causing inhibitory ef-
therapy is needed. fects on pain responses. Furthermore, endocannabinoids
(iv) Consider capsaicin cream for patients with localised NeP have been shown to interact with other receptor systems
who are intolerant to or wish to avoid oral medications. including g-aminobutyric acid, serotonergic, adrenergic and
(v) Carbamazepine is the first-line drug for TGN. Early opioid receptors, many of which are involved in the analgesic
specialist referral required if it is not effective or mechanisms of medications commonly used for NeP.7
tolerated. Tetrahydrocannabinol (THC) is the component in cannabis
(vi) Do not start the following in a non-specialist setting, responsible for its therapeutic effects. Another component,
unless advised by a specialist: cannabis sativa extract, cannabidiol (CBD), has a possible additive effect, and is
capsaicin patch, lacosamide, lamotrigine, levetiracetam, thought to decrease the psychoactive effects of THC.5 Signif-
morphine, oxcarbazepine, topiramate, venlafaxine, and icant adverse events are rare and include headache, confu-
long-term tramadol. sion, agitation, and paranoid ideation. In one trial the number
of patients with adverse events decreased during treatment,
suggesting increased tolerance over time. Long-term safety
Revised 2015 IASP Neuropathic Pain Specialist
data for use in NeP are limited. One-year follow-up reported
Interest Group recommendations
predominantly GI adverse effects and an increased risk of
Grading of Recommendations Assessment, Development, and chronic bronchitis with cannabis use.7
Evaluation (GRADE) is an internationally accepted method to In the past decade, the use of cannabis and selective
provide new evidence-based recommendations (http:// (synthetic) cannabinoids has gained popularity for the treat-
www.gradeworkinggroup.org.). Using GRADE, the Neuro- ment of NeP. There has been no consensus on the role of se-
pathic Pain Specialist Interest Group (NeuPSIG) of the IASP lective cannabinoids in NeP, with contradictory
revised its previous recommendations (Table 2). The NeuPSIG recommendations from both national and international pain
recommendations are more applicable to the chronic pain societies. The Canadian Pain Society has advised selective
specialist setting4 (See Table 2). cannabinoids as third-line agents for NeP.7,8 It recommends
close monitoring with long-term treatment and quotes his-
tory of psychosis as a contraindication.7,8 NeuPSIG has rec-
How do these recommendations differ from previous NeuPSIG
ommended against use of cannabinoids because of weak
recommendations?
evidence.7
(i) Gabapentin enacarbil (extended release) and duloxetine THC may not be an effective analgesic on its own, but it has
are now added as first-line treatments along with tricy- a pronounced synergistic effect when combined with opioids
clic antidepressants and regular gabapentin. and may play a role in weaning patients from high-dose opi-
(ii) Lidocaine plaster is no longer first-line because the evi- oids. Selective cannabinoids may therefore have a role as
dence is weak. It remains second-line for peripheral NeP combined analgesic therapy for refractory NeP (GRADE: weak
because it has an excellent safety profile. Where there recommendation, moderate quality evidence).7
are safety concerns with first-line treatments, lidocaine The first systematic review and meta-analysis on the
plaster can still be considered as first-line. analgesic efficacy of selective cannabinoids as adjuncts in
(iii) Strong opioids are now third-line because of weak evi- relieving refractory central and peripheral NeP was published
dence (previously first or second-line). in 2017.7 Seventeen percent of patients were unable to tolerate

278 BJA Education - Volume 18, Number 9, 2018

 Table 1 Evidence summary from meta-analysis as the basis for the updated NICE recommendations.3Table 1

Drug Daily dose Number needed 95% Confidence Number needed 95% Confidence Evidence Safety Number of trials in meta-analysis
to treat interval to harm interval quality profile

Antidepressants
Amitriptyline 25e150 mg 3.6 3.0e4.4 13.4 9.3e24.4 Moderate 18
N.B. No evidence
of a doseeresponse
effect
SNRIs Duloxetine 20e120 mg 6.4 5.2e8.4 11.8 9.5e15.2 High 14
Venlafaxine 150e225 mg (combined) (combined)
Anticonvulsants
Pregabalin 150e600 mg 7.7 6.5e9.4 13.9 11.6e17.4 High 25
N.B. Doseeresponse
gradient exhibited
Gabapentin 900e3600 mg 6.3 5.0e8.3 25.6 15.3e78.6 Good 14
N.B. No doseeresponse
effect
Gabapentin enacarbil 1200e3600 mg 8.3 6.2e13.0 31.9 17.1e230.0 Good 14
(extended release) N.B. No doseeresponse
effect
Topiramate 6.3 3.6e6.7 Poor
Zonisamide 2.0 1.3e4.6 Poor
Oxcarbazepine 5.5 4.3e7.9 Poor
Weak opioid agonist/SNRI
Tramadol/Tramadol Up to 400 mg 4.7 3.6e6.7 12.6 8.4e25.3 Moderate 7
extended release
BJA Education - Volu18, Number 9, 2018

Mu-opioid agonist/noradrenaline reuptake inhibitor

Tapentadol 10.2 5.3e185.5 2
Strong opioids Oxycodone 10e120 mg 4.3 (combined) 3.4e5.8 11.7 (combined) 8.4e19.3 Moderate 13
Morphine 90e240 mg N.B. Type of pain ¼ mainly peripheral
N.B. Maximum effectiveness neuropathic
associated with 180 mg
morphine or equivalent
Capsaicin 8% patch (showed sustained 10.6 7.4e18.8 High 7

Treatments for neuropathic pain

efficacy compared with N.B. Type of pain ¼ post-herpetic
0.04% cream) neuralgia and HIV-related painful
polyneuropathy
Botulinum Botulinum toxin Aa 1.9 1.5e2.4 Good 6
50e200 units (administered N.B. Type of pain¼peripheral neuropathic
s.c. in the region of pain)

NICE, National Institute for Health and Care Excellence; SNRI, selective serotonin and norepinephrine reuptake inhibitor.
a
Potent neurotoxin, may have analgesic effects by its action on neurogenic inflammation; a mechanism that may be involved in some peripheral neuropathic pain conditions.16.
279
Treatments for neuropathic pain

Table 2 NeuPSIG recommendations based on the GRADE classification.2Table 2

Drug Total daily dose and dose regimen GRADE Tolerability and safety Cost
strength of
recommendation

First line
Gabapentin 1200e3600 mg, in three divided doses STRONG Moderateehigh Lowemoderate
Gabapentin extended 1200e3600 mg, in two divided doses STRONG Moderateehigh Lowemoderate
release or enacarbil
Pregabalin 300e600 mg, in two divided doses STRONG Moderateehigh Lowemoderate
SNRIs, duloxetine, or Duloxetine 60e120 mg STRONG Moderate Lowemoderate
venlafaxinea Venlafaxine extended release
150e225 mg
TCAsb 25e150mg, once a day or in two divided STRONG Lowemoderate Low
doses
Second line
Capsacin 8% patchesc 1e4 patches to the painful area for WEAK Moderateehigh Moderateehigh
N.B. Indication ¼ peripheral 30e60 min every 3 months N.B. Potential safety
neuropathic pain concerns over sensation
with longeterm use
Lidocaine plasters 1e3 5% plasters to region of pain one per WEAK High Moderateehigh
N.B. Indication ¼ peripheral day for up to 12 h
neuropathic pain
Tramadol 200e400 mg, in three divided dose (or WEAK Lowemoderate Low
two for extended release)
Third line
Botulinum toxin A 50e200 units to the painful area every 3 WEAK
N.B. Specialist use, months
Indication ¼ peripheral
neuropathic pain, third
line because the quality
of evidence is weak
Strong opioids Individual titration WEAK
Recommendations AGAINST use
Cannabinoids WEAK
N.B. Because of negative
trial results, potential
misuse, diversion,
long-term mental
health risks
Valproate WEAK
Levetiracetam STRONG
N.B. Because of generally
negative trials and
safety concerns
Mexiletine STRONG
N.B. Because of generally
negative trials and
safety concerns

Sustained-release oxycodone and morphine are the opioids most studied. Long-term use may be associated with abuse, cognitive impairment, and
endocrine and immunological changes. Prescription requires risk assessment strict monitoring and treatment agreements. GRADE, Grading of Recom-
mendations Assessment, Development, and Evaluation; SNRI, selective serotonin and norepinephrine reuptake inhibitor; TCA, tricyclic antidepressants.
a
Duloxetine is the most studied and therefore the most recommended SNRI.
b
The tertiary amine TCAs (amitriptyline, imipramine, clomipramine) are not recommended at doses greater than 75 mg day#1 in >65 yr because of
major anticholinergic and sedative adverse effects, and an increased risk of sudden cardiac death at doses >100 mg day#1.
c
The long-term safety of repeated application of high-concentration capsaicin patches is not clearly established. They may exacerbate progressive
neuropathy by degeneration of epidermal nerve fibres.

the maximum allowed dose, therefore potentially preventing Sequential combination therapies
attainment of therapeutic levels.
Combination of two or more analgesics have been recom-
Typical daily dosing regimens:
mended by the WHO, the American Pain Society (APS), and
! Nabilone (oral, 1e4 mg) the American College of Rheumatology (ACR).1 Monotherapy
! Dronabinol (oral, 2.5e10 mg) with current agents can have limited efficacy even when
! Nabiximols [oromucosal THC-CBD spray, range 1e48 maximum doses are reached, and with dose-related adverse
sprays (mean 8.3 sprays)] effects. Combination therapy with two or more different
! Cannabis (smoked or vaporised medical marijuana, con- drugs may improve efficacy, as the aetiology of NeP is related
taining 1.875e34 mg THC). to more than one biochemical pathway.1,4 The overall inci-
dence of adverse effects can be reduced, particularly if the
These doses were associated with a significant reduction in
combination displays synergism, thus allowing for decreased
mean numerical rating scale (NRS) scores, improved Quality of
dosages.4
Life (QoL) measures, sleep, and patient satisfaction.

280 BJA Education - Volume 18, Number 9, 2018

 Treatments for neuropathic pain

COMBO-DN study regimen in this study was 3.9 mg daily (0.65 g doses, applied to
both feet three times per day). Plasma clonidine concentra-
The COMBO-DN study is a multinational trial designed to
tions in subjects were generally below the lower limit of
answer the common clinical question: ‘Is it better to increase
detection (10 pg ml#1) compared with the typical plasma
the dose of the current first-line recommended monotherapy
concentrations attained in the treatment of hypertension
or to combine with another first-line recommended drug early
(1000 pg ml#1). Therefore the action of topical clonidine is
on in patients with insufficient pain relief?’
thought to be mediated peripherally.13
In the trial, the efficacy and tolerability of maximal dose
monotherapy (either duloxetine 120 mg day#1 or pregabalin
600 mg day#1) was compared to a combination regimen with Topical ketamineegabapentineimipraminee
lower dosages. The study group was patients with PDN who bupivacaine
had not previously responded to the standard dose of either Topical creams with multiple anti-NeP agents have been
pregabalin or duloxetine. successful in treating NeP. They act multi-modally to reduce
The results consistently favoured combination therapy, sensation via pain nerve fibres by targeting multiple receptors
supporting the theory that pharmacotherapies with differing simultaneously. An anti-NeP topical cream with ketamine
mechanisms of action may complement each other and have 10%, gabapentin 10%, imipramine 3%, and bupivacaine 5%
additive effects in clinical practice.9 was shown to resolve NeP symptoms for several hours; it was
also successful in reducing flare-ups in a patient with cervi-
calgia and TGN, refractory to several treatments.10 Ketamine
Cochrane review 2012
and gabapentin are more effective together as they mitigate
This review demonstrated the superior efficacy of two-drug glutaminergic calcium influx more effectively in combination.
combinations. RCTs have proved that gabapentinemorphine These agents offer effective non-invasive, non-systemic
and nortriptylineepregabalin yield greater efficacy when therapy, but with the limitation of the cost required for the
applied together; hence anticonvulsanteopioid and compounding process.14
antidepressanteanticonvulsant combinations have been rec-
ommended for NeP. A further trial has shown that an
antidepressanteopioid combination in the form of Interventional treatments
nortriptylineemorphine was superior to monotherapy.10,11
Erector spinae plane block
Ideally, combinations of drugs that have similar adverse
The ESP block is a novel technique in the treatment of thoracic
effect profiles should be avoided, so combination therapy in
NeP. It is an interfascial plane block. Local anaesthetic is
clinical practice requires vigilance. One common approach to
administered deep to the erector spinae muscle in order to
reduce the risk of toxicity is ‘sequential combination therapy’.
gain proximity to dorsal and ventral rami of the thoracic spi-
Patients are first commenced on monotherapy. If only a par-
nal nerves. It has been successful in severe cases of refractory
tial response to treatment is observed, the patient receives
NeP, producing an extensive multi-dermatomal sensory
add-on therapy. This may be subsequently lead to differing
block, both posteriorly and anteriorly. In comparison, the
dose ratio than might have otherwise been attained. Future
pectoral and serratus plane block provide only anterior
research should aim to clarify the optimal ratios and therefore
coverage. It has easily recognisable sonoanatomy and lends
cost-effectiveness.10
itself to the insertion of an indwelling catheter.15

Novel techniques Dorsal root entry zone ablation treatments

Pharmacotherapy delivery Dorsal root entry zone (DREZ) procedures are indicated in
complex and resistant segmental, and more recently, diffuse
Domiciliary s.c. lidocaine
NeP after complete spinal cord injury. Alternative ap-
Systemic intravenous lidocaine is well established in the
proaches such as neuromodulation require a permanent
treatment of NeP. A single infusion can provide relief for
prosthetic implant. DREZ targets nociceptive fibres in the
several weeks to months. Some patients experience dramatic
lateral bundle of the dorsal rootlet, the deafferented neurons
but brief pain relief. However, it is impractical and costly to
in the dorsal horn, and the medial portion of the Lissauer
provide very frequent infusions. Subcutaneous lidocaine has
tract.16
shown promising results in providing continual analgesia,
with no adverse events, no difficulties with self-injection, and
high patient acceptability.12 Self-administration of s.c. lido- Deep brain stimulation
caine may substantially reduce healthcare costs. Deep brain stimulation (DBS) has been used in refractory
chronic pain for many decades. Standard DBS can be inef-
Topical treatments fective as not all patients respond to stimulation along pri-
The use of topical treatment in managing NeP is becoming mary sensory pathways. In 2014, the first case series of DBS of
increasingly popular. the anterior cingulate cortex (ACC) to target the affective
component of pain was described. Twenty-four patients un-
Topical clonidine derwent bilateral ACC DBS. Inclusion criteria included failed
Alpha2 receptors in nociceptors are expressed within the pharmacotherapy for at least 2 yr or failed standard DBS. Six
epidermis and are associated with increased nociceptor months after surgery the mean NRS pain score decreased
excitability. Topical clonidine, an a2 adrenergic agonist, tar- from 8.0 to 4.27 (P¼0.004). Patients described that pain was still
gets these receptors. In patients with PDN with functional present but less bothersome. Efficacy was sustained for up to
nociceptors in the affected areas, clonidine topical gel has 42 months. ACC DBS can improve QoL and alleviate otherwise
been shown to significantly reduce pain levels. The dosing treatment-resistant chronic NeP.17

BJA Education - Volu18, Number 9, 2018 281

Treatments for neuropathic pain

Pain phenotyping neuropathic than nociceptive pain. In preclinical testing it

showed antinociceptive, antihyperalgesic, and antiallodynic
Clinical phenotyping describes the process of identifying
actions, with significantly higher potency than morphine. The
relevant clinical criteria and classifying patients into corre-
adverse effect profile of cebranopradol is favourable
sponding subgroups. It is assumed that the different sub-
compared with morphine at equianalgesic doses; it also has
groups have varying underlying pain mechanisms, and
lower incidences of opioid-induced respiratory depression
therefore may respond differentially to treatments.5
and pruritus, and delayed onset of tolerance. In addition, NOP
Our current way of classifying NeP is generally inadequate.
agonism reduces dopamine release from neurones involved in
Regardless of aetiology, patients should be classified accord-
reward pathways. Thus the combination of NOP and MOP (m-
ing to their clinical phenotype. This is now facilitated by
opioid peptide) receptor agonism may attenuate opioid
validated NeP questionnaires and standardisation of sensory
reward pathways in a similar manner to buprenorphine. The
testing, such as quantitative sensory testing (QST). One
results of phase III clinical trials are awaited.1
example describes the presence of mechanical allodynia
depicting preserved nociceptive function. This can predict
response to various treatments including sodium channel Angiotensin II type 2 receptor antagonists
blockers, clonidine gel, and botulinum.
In the past two decades, there has been a collaborative global
The COMBO-DN trial demonstrated that patients with
research effort on the pathophysiology of NeP. This has
certain clinical phenotypes predicted clinical response to
revealed a multitude of ‘pain targets’ including receptors,
duloxetine or pregabalin, either alone or in combination.9
enzymes, and ion channels. Despite promising results in an-
Patients with pressing and evoked pain not responding to a
imal models this failed to translate into humans. One excep-
standard dose of duloxetine showed improvement when a
tion is the AT2 receptor antagonists, which represent a
standard dose of pregabalin was added to the regimen.
completely new analgesic class. EMA401 is a first-in-class
Conversely patients describing pain with characteristics of
orally active, highly selective, peripherally restricted AT2 re-
paraesthesia and dysaesthesia received benefit from max-
ceptor antagonist that has been successful in a clinical proof-
imising the dose of duloxetine. Patients with peripheral NeP
of-concept trial in patients with postherpetic neuralgia.8
with preserved thermal sensation responded positively to
botulinum toxin A. A higher therapeutic response correlated
with less severe thermal deficits. In the future, it may be
Conclusion
possible to incorporate therapeutic algorithms such as this,
which could be fundamental in predicting therapeutic re- The treatment of NeP is complex, and as such it would be
sponses and thus reduce the incidence of therapeutic impossible to suggest a specific ‘neuropathic pain ladder’. In
failures.5 general, a multimodal approach is adopted, recognising the
requirement of the biopsychosocial approach to these
patients.
Mechanistic updates Recommended first-line treatments are the gabapentinoids
(gabapentin, pregabalin), and antidepressants (duloxetine,
Additional insights into antidepressants and
amitriptyline). It is important to recognise when treatment is
gabapentinoids
not successful and switch medication early, rather than up-
The onset of therapeutic effects of antidepressants is delayed. titrating. It should be borne in mind that patients may
Hence their action is thought to be via long-term molecular benefit from combination therapy. This should be trialled
and neural plasticity, recruiting downstream mechanisms early, with emerging evidence of efficacy and tolerability of
such as chromatin regulation, gene expression, recruitment of moderate doses compared with maximal dose monotherapy.
neurotrophins, and stimulating neurogenesis. Antidepressantegabapentinoid, antidepressanteopioid, and
The action of antidepressant drugs on noradrenaline is a gabapentinoideopioid are supported combinations. Local
crucial component in the treatment of NeP. There are two anaesthetic blocks and more invasive procedures tend to be
proposed mechanisms for this: recruitment of descending reserved as an adjunct to pharmacotherapy, or in those pa-
noradrenergic pathways and peripheral noradrenaline tients refractory to it.
recruitment from sympathetic nerves in the dorsal root Tapentadol targets both nociceptive and neuropathic
ganglia. They may also act indirectly on proinflammatory pathways and has been in clinical use in certain patient
cytokines.18 groups and geographical locations since 2011. It tends to be
Gabapentinoids also activate this inhibitory descending reserved for those in whom morphine has proved inadequate
noradrenergic pathway. In addition, like antidepressants, or not tolerated. The opioid cebranopradol is an exciting
they may impact on proinflammatory cytokines. In compari- prospect in the treatment of chronic NeP, but more data are
son to the slow onset of antidepressants, the acute adminis- needed.
tration of gabapentinoids at high doses demonstrates efficacy
against NeP.18
Declaration of interest
The authors declare that they have no conflicts of interest.
Future perspectives
Cebranopradol
This is a promising unique, centrally-acting agent. It is a single
MCQs
molecule but has dual agonist action at opioid and noci- The associated MCQs (to support CME/CPD activity) will be
ception/orphanin FQ peptide (NOP) receptors.1 Compared accessible at www.bjaed.org/cme/home by subscribers to BJA
with traditional opioids, cebranopradol is more potent against Education.

282 BJA Education - Volume 18, Number 9, 2018

 Treatments for neuropathic pain

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