PAIN
Pharmacology in the
management of chronic
pain
Matthew Roe
Arun Sehgal
Abstract
Management of chronic pain should be achieved with a bio-
psychosocial approach and often requires multidisciplinary input.
Pharmacological treatment can play an important role in the success-
ful management of chronic pain. When planning a pharmacological
strategy for chronic pain it is important to consider the nature and
likely source of the pain. This review article will summarize common
pharmacological options in current clinical use for the management
of chronic pain.
Keywords Chronic pain; pharmacological treatment
Royal College of Anaesthetists CPD Matrix: 2E03
Outline
Pain management strategies show considerable overlap between
those categorized as acute and chronic pain; chronic pain being
that which is present for greater than 12 weeks.1 Additionally,
there may be causative overlap i.e. acute pain following surgery
or trauma has been shown to progress to chronic pain in as many
as 50% of cases while other cases of chronic pain may not have
an obvious precipitant.
When deciding upon a pharmacological strategy for chronic
pain it is important to consider the nature and likely afferent
source of the pain e.g. deep viscus versus superficial wound
pain, nociceptive versus neuropathic. We can then target and
rationalize the agents appropriately. We will often employ a
multi-modal approach to treatment, meaning the use of a
number of different agents perhaps acting at differing pain re-
ceptor sites. There is evidence that this approach can be bene-
ficial in acute post-operative pain but there may be increased
likelihood of poor medicine compliance in chronic pain. The aim
of a multi-modal strategy is to gain a degree of synergism be-
tween agents or to perhaps gain the most benefit from each drug
while reducing its dosage and subsequent side effects.
Matthew Roe FRCA is a Specialty Registrar in the Department
of Anaesthesia and Pain Medicine at Peterborough and
Stamford Hospitals, Peterborough, UK. Conict of interest:
none declared.
Arun Sehgal FRCA FFPMRCA MD DNB is a Consultant in the
Department of Anaesthesia and Pain Medicine at Peterborough
and Stamford Hospitals, Peterborough, UK. Conict of interest:
none declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 17:11
Learning objectives
After reading this article, you should be able to:
C discuss the general principles of use of pharmacological treat-
ment in chronic pain
C describe the mechanisms of action of most commonly used
pharmacological agents
C outline the evidence base for these drugs
Specic medications
Paracetamol
Paracetamol was first introduced into medical practice in the late
19th century but its popularity did not really increase until the
middle of the 20th century. The use of paracetamol is almost
universal as a routine analgesic for acute and chronic pain due to
its perceived low side effect profile, low cost and availability in
oral, intravenous and rectal preparations. Despite its widespread
use, its mechanism of action is still not fully understood. While
urinary prostaglandin metabolites are reduced following admin-
istration of paracetamol, synthesis of prostaglandins is un-
changed. It is thought that the mechanism of action may be via
cyclo-oxygenase (COX)-3 inhibition as paracetamol is known to
be a weak inhibitor of both COX-1 and COX-2. Because of this it
has traditionally been regarded as an NSAID, although it differs
from other commonly used NSAIDs particularly in its side effect
profile. While its potential COX inhibition explains the anti-
pyretic and weak anti-inflammatory properties it doesnt fully
explain its analgesic action. Studies have demonstrated periph-
eral as well as central activity through prostaglandin, 5-HT2 and
5-HT3 receptors.2 The mechanism of action of paracetamol is an
ongoing area of research and may yet yield a better under-
standing of this drug.
The evidence for efficacy in chronic pain, particularly with
chronic back pain is particularly limited with only small and
inconclusive trial data available.3 It has little effect in neuro-
pathic pain although some benefit has been seen when combined
with a weak opioid such as codeine or tramadol.4 It has been
shown that the combination of paracetamol and ibuprofen is
superior to paracetamol alone for chronic knee pain. However,
one must be cautious of the side effects of regular and long term
use of NSAIDs (see below).
NSAIDs
The primary mechanism of action of the NSAIDs is mainly due to
inhibition of cyclo-oxygenases which are usually involved in the
formation of prostaglandins. Prostaglandins are involved in pain
pathways at a number of sites both centrally and peripherally in
the pain pathway. Inhibition of prostaglandin formation will
therefore reduce the inflammatory effect of prostaglandins and
subsequently modulate pain thresholds. The two most clinically
important forms of COX isoenzyme (1 and 2) have different
biological functions with the majority of the analgesic action
seemingly being mediated by COX-2 inhibition. It was an attempt
to avoid the gastrointestinal side effects of COX-1 inhibition that
led to the development of selective COX-2 inhibitors e the
548 2016 Published by Elsevier Ltd.

coxibs. Their use has since been curtailed following evidence of
increased risk of myocardial infarction and other thrombotic
events.
The risks of GI disturbance, renal and cardiovascular disease
must be considered and therefore their use should be subject to
very careful consideration of dose and duration of treatment.
NSAIDs may be contraindicated in those with vascular diseases
of the heart, brain and renal system. Caution is advised in pa-
tients with cardiac risk factors (smoking, diabetes, raised
cholesterol or hypertension.)
Recent work has suggested NSAIDs may also work by a COX-
independent mechanism. The NSAIDs may be able to penetrate
cellular membranes and affect a variety of intra-cellular pro-
cesses. One such process involves interfering with L-selectin
within neutrophils.5 L-Selectin is a chemical that is involved in
the inflammatory response of the neutrophil and therefore the
subsequent sensitization to pain in inflammatory conditions.
There is evidence supporting NSAID use in chronic low back
pain. However, there is seemingly no added benefit from using
COX-2 selective NSAIDs over non-selective NSAIDs.6 There does
seem to be a place for topical NSAIDs in chronic joint pain
conditions with a NNT of 11 for topical Diclofenac gel and none
of the potential adverse gastrointestinal risks when compared
with enteral therapy.7 A Cochrane review recently examined the
use of NSAIDs in neuropathic pain conditions as the use of
NSAIDs in this area has been reported to be nearly 50%.8 The
review reported that the trial data supporting the use of NSAIDs
for neuropathic pain was of poor quality and failed to conclude
either way whether NSAIDs are of use in neuropathic pain con-
ditions. This remains an area of future research interest and the
findings of the Cochrane review are unlikely to alter the NSAID
use for many patients with chronic neuropathic pain.
Anticonvulsants
The anticonvulsant drugs in use for treating chronic pain act via
calcium channel blockade, sodium channel blockade, interfer-
ence in glutamatergic transmission or a combination of these
mechanisms.
The use of gabapentin in the perioperative period has become
increasingly common as many of the agents used in chronic pain
management are finding a place in the acute post-surgical arena.
Although initially designed as anticonvulsants, the gabapenti-
noids (which include pregabalin and gabapentin) have signifi-
cant analgesic properties. Their analgesic activity is likely to
come via selective inhibition of a voltage gated calcium channel
containing the a2d-1 subunit.
A single preoperative dose of gabapentin has been shown to
reduce opioid use by up to 60% for the first 24 hours after sur-
gery but there is a need for further work to pinpoint specific
surgical procedures that may benefit most. Additionally, it is
uncertain as to the optimal dose and whether they need to be
continued post-operatively. It has particular possibility in
reducing the development of chronic post-surgical pain (CPSP).
A recent systematic review found that the gabapentinoids
showed greatest promise with breast surgery but the trials
included in the study found them to be ineffective for amputa-
tions or cardiac surgery which are two of the other high-risk
procedures for developing CPSP.9
ANAESTHESIA AND INTENSIVE CARE MEDICINE 17:11
PAIN
Gabapentin is recommended in the treatment of chronic
neuropathic pain where it is has proven effectiveness particularly
in post-herpetic neuralgia and painful diabetic neuropathy. The
evidence supporting its use in fibromyalgia is less convincing. At
daily doses of 1200 mg or more it demonstrates a NNT of be-
tween 5 and 8.3 for neuropathic pain conditions. Its use can,
however, be associated with drowsiness, oedema, dizziness,
weight gain and gait disturbance causing around one in 10 people
to stop taking the medication.
In chronic neuropathic conditions pregabalin is generally
reserved for those patients in who first-line therapy has not been
tolerated. Doses of 300e600 mg daily have been shown to be
effective in various types of neuropathic pain. It has a similar
side effect profile to gabapentin. A recent meta-analysis as well
as the current NICE guidance both strongly recommended
gabapentinoids as first line treatment in neuropathic pain.10,11
Pregabalin can cause side effects similar to gabapentin.
In the treatment of chronic neuropathic pain carbamazepine,
which primarily acts via inhibition of sodium channels leading to
neuronal suppression, has proven very effective with a NNT of
1.7. It is commonly used in patients with trigeminal neuralgia at
doses up to 1600 mg daily. The study data demonstrating its
effectiveness has not been of the highest quality. Around two-
thirds of patients using carbamazepine reported good pain relief
in the short term although the same number also experienced at
least one side effect.10 The potential side effects include throm-
bocytopenia, leukopenia, hyponatraemia, somnolence, dizzi-
ness, headache, ataxia, nystagmus, diplopia, blurred vision,
hepatotoxicity (Table 1).
Antidepressants
There is potential that drugs that up-regulate the noradrenergic
and serotonergic systems such as tricyclic antidepressants
(TCAs), selective serotonin uptake inhibitors (SSRIs) and sero-
tonin noradrenergic reuptake inhibitors (SNRIs) could be of
benefit in chronic pain. The evidence is that the TCAs and SNRIs
have greater efficacy than SSRIs for neuropathic pain. The SNRIs
in common clinical practice include venlafaxine and duloxetine.
They have been shown to be efficacious in fibromyalgia,12
painful diabetic neuropathy10 and painful osteoarthritis of the
knee.13 With regards to osteoarthritis of the knee, duloxetine has
been shown to be as effective as NSAIDs for analgesia and is now
a recommended treatment for this patient group. In terms of the
Anticonvulsants
Gabapentin NNT of between five and 8.3 for
neuropathic pain
Moderate benefit in preventing
development of chronic post-surgical pain
Pregabalin NNT of around five for post-herpetic
neuralgia and diabetic neuropathy
Moderate benefit in preventing
development of chronic post-surgical pain
Carbamazepine NNT of 1.7 in trigeminal neuralgia
Table 1
549 2016 Published by Elsevier Ltd.

potential for developing chronic post-surgical pain where mas-
tectomy is considered to be one of the high-risk procedures
alongside thoracotomy and amputation, venlafaxine has shown
to be superior to the gabapentinoids.9
Tricyclic antidepressants such as amitriptyline or nortripty-
line have common usage in post-herpetic neuralgia, painful
diabetic neuropathy and fibromyalgia. There is little good quality
evidence to support their use in chronic low back pain. There is
evidence that amitriptyline used in the acute pain episode of
herpes zoster infection can reduce the likelihood of developing
post-herpetic neuralgia. One must be cautious in initiating TCA
therapy in elderly patients as this group of medicines may have
enhanced anti-cholinergic activity that could result in cognitive
dysfunction.
The COMBO-DN study in 2013 compared high-dose mono-
therapy with duloxetine or pregabalin with a combination of
these two agents in patients with diabetic peripheral neuropathic
pain. Overall the study authors concluded that combination
therapy was safe and effective but demonstrated no significant
advantages over standard dose mono-therapy14 (Table 2).
Topicals
In patients with post-herpetic neuralgia or HIV neuropathy, an
8% topical capsaicin patch has been shown to be effective.10
Intravenous and topical lidocaine was shown to be effective in
acute and chronic pain and its benefits may be related to mod-
ulation of the neuroinflammatory response to pain.15 It has
specific uses in the prevention of CPSP after mastectomy and in
fibromyalgia.16 Lidocaine and capsaicin patches are recom-
mended as second line agents in neuropathic pain. Lidocaine 5%
plaster can be of benefit in localized neuropathic pain such as
post-herpetic neuralgia10 (Table 3).
Ketamine
Ketamine is an NMDA receptor antagonist with significant
analgesic and opiate sparing properties. As the NMDA system is
important in the development of central sensitization, down-
regulation of the pathways by ketamine may reduce the inci-
dence and severity of chronic pain conditions such as CPSP and
opioid-induced hyperalgesia. Indeed it has been shown that
intra-operative ketamine can reduce the likelihood of developing
chronic post-surgical pain.17 This effect was most evident
following laparotomy, thoracotomy and hip arthroplasty but not
Antidepressants
Tricyclics Neuropathic pain NNT 2e3.
Potential efficacy in fibromyalgia.
Reduced incidence of post-herpetic
neuralgia when used in acute phase
Serotoninenorepinephrine Neuropathic pain NNT 5e6. Venlafaxine
reuptake inhibitors given for 10 days post mastectomy
reduces incidence of CPSP at 6 months
Serotonin selective Neuropathic pain NNT 6.8. May offer
reuptake inhibitors sleep and mood benefits for
fibromyalgia but little effect on pain
Table 2
ANAESTHESIA AND INTENSIVE CARE MEDICINE 17:11
PAIN
Topical agents
Topical lidocaine Better than placebo for post-herpetic
neuralgia
Topical NSAIDs NNT of 11 for gel
Better than placebo for osteoarthritis of hand
or knee
Topical capsaicin (8%) Evidence supporting its use in post-herpetic
neuralgia and HIV neuropathy
Table 3
seen with amputation, knee arthroplasty or hysterectomy.
However, NICE guidance from 2014 concluded that there was no
good quality evidence to support the use of oral ketamine to treat
chronic pain in adults and that the study data available for young
people was not sufficiently powerful to draw any firm
conclusions.18
Opioids
A small proportion of individuals with chronic pain may benefit
from the use of opioids. There is little evidence for their efficacy
for long term pain relief. Opioids are used either as oral prepa-
rations or transdermal patches. Commonly used oral prepara-
tions include codeine, tramadol, morphine, oxycodone,
tapentadol and the transdermal patches are buprenorphine and
fentanyl.
There is no good evidence of doseeresponse with opioids,
beyond doses used in clinical trials, usually up to 120 mg/day
morphine equivalent.19 Many patients discontinue long-term
opioid therapy (especially oral opioids) due to adverse events or
insufficient pain relief. For further details on use of opioids in
pain management please see pages 552-554 of this issue.
Summary
 It is important to consider the likely afferent source of the
pain.
 Discuss drug treatment limitations and manage expecta-
tions of pain relief as part of the overall management plan.
 Regular review and reassessment is important with
awareness of variation of efficacy and possible side effects.
Stop or change medication that is not working effectively.
 Due to different mechanisms of pain transmission and
mechanism of action of drugs, individuals with chronic
pain, particularly neuropathic pain, often require a com-
bination of analgesics.
 Combination therapy may help reduce the side effects from
high doses of individual drugs.
 It is recommended that patients with neuropathic pain
conditions excluding trigeminal neuralgia are offered a
choice of amitriptyline, duloxetine, gabapentin or pre-
gabalin as the initial pharmacological treatment. In situa-
tions where the first line agent is not successful then the
medication should be switched between these four drugs.
 In the case of trigeminal neuralgia, carbamazepine is the
recommended first line agent. Potential rescue therapies
available if these initial options fail include tramadol and
capsaicin cream.10,11
550 2016 Published by Elsevier Ltd.
 PAIN

Pharmacological treatment can play an important role in the 11 NICE Guideline [CG173] Neuropathic pain in adults: pharmaco-
management of patients with chronic pain and should be pre- logical management in non-specialist settings. Published
scribed as part of a biopsychosocial approach to pain. A November 2013. Available at: http://www.nice.org.uk/guidance/
CG173/chapter/1-Recommendations#list-of-all-
recommendations. (accessed 19 May 2016).
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ANAESTHESIA AND INTENSIVE CARE MEDICINE 17:11 551 2016 Published by Elsevier Ltd.