Review Article

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Adjuvant analgesics
Neha Gupta1, Amy Allen Case2
1

University of New York at Buffalo School of Medicine and Biomedical Sciences, Palliative Medicine Fellow, VA Western New York Healthcare

System, Buffalo, NY 14214, USA; 2State University of New York at Buffalo School of Medicine and Biomedical Sciences, VA Western New York
Healthcare System, Buffalo, NY 14214, USA
Correspondence to: Amy Allen Case, MD, Hospice and Palliative Medicine Fellowship Program Director, Assistant Professor of Medicine, Palliative
Medicine Director. State University of New York at Buffalo School of Medicine and Biomedical Sciences, VA Western New York Healthcare System,
Buffalo, NY 14214, USA. Email: amy.case@va.gov.

Abstract: Chronic pain is a global problem. Estimates suggest an adult worldwide prevalence of 20%
(120 million). The most effective treatment strategy for chronic pain is a multimodal and balanced
approach combining pharmacologic and non-pharmacologic treatments. Adjuvant analgesics are a diverse
group of drugs that have a primary indication for use other than for pain, but have been found to have
analgesic properties in some pain conditions. They often are co-administered with traditional analgesics
and sometimes referred to as co-analgesics. Major classes of adjuvant analgesics include antidepressants,
antiepileptic drugs (AED), corticosteroids, alpha (2) adrenergic agonists, N-methyl D-aspartate (NMDA)
receptor antagonists, gamma amino butyric acid (GABA) agonists, local anesthetics, topical analgesics,
benzodiazepines, neuroleptics, muscle relaxants, bisphosphonates, cannabinoids, psycho-stimulants, anticholinergics, calcitonin, radiopharmaceuticals and octreotide. There are numerous pharmacotherapeutic
options for the management of chronic pain. Proper evaluation, along with complete assessment of pain, is
crucial to provide best possible analgesic approach.
Keywords: Analgesics; chronic pain; pain management; co-analgesics
Received: 08 June 2016; Accepted: 21 June 2016; Published: 28 June 2016.
doi: 10.21037/phe.2016.06.14
View this article at: http://dx.doi.org/10.21037/phe.2016.06.14

Introduction
Chronic pain is a global problem. Estimates suggest an adult
worldwide prevalence of 20% (120 million). Additionally,
the prevalence of new diagnoses is 10% (60 million) each
year. One in three elderly adults have difficulty living
independently due to chronic pain (1). Chronic pain should
be recognized as not just a symptom, but as a disease
itself. The most effective treatment strategy for chronic
pain is a multimodal and balanced approach combining
pharmacologic and non-pharmacologic treatments.
Adjuvant analgesics are a diverse group of drugs that
have a primary indication for use other than for pain, but
have been found to have analgesic properties in some pain
conditions. They often are co-administered with traditional
analgesics and sometimes referred to as co-analgesics.
Even though these agents mainly are used as adjuvants in

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various pain conditions, some adjuvant analgesics also are

being used as a first-line treatment option for management
of specific pain, e.g., gabapentin for neuropathic pain. Using
an adjuvant analgesic is important to the success in effective
pain management.
Before using an adjuvant analgesic for pain control,
providers must be familiar with the drugs clinical
pharmacology, approved indications and off-label use,
common side effects, drug interactions and specific
dosing guidelines. Major classes of adjuvant analgesics
include antidepressants, antiepileptic drugs (AED),
corticosteroids, alpha (2) adrenergic agonists, N-methyl
D-aspartate (NMDA) receptor antagonists, gamma amino
butyric acid (GABA) agonists, local anesthetics, topical
analgesics, benzodiazepines, neuroleptics, muscle relaxants,
bisphosphonates, cannabinoids, psycho-stimulants,
anti-cholinergics, calcitonin, radiopharmaceuticals and

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Table 1 Adjuvant analgesics: major classes of drugs

Class of drug

Example

Antidepressants

Indication for type of pain

Multipurpose analgesics

TCAs

Amitriptyline, nortriptyline, desipramine

SSRIs

Paroxetine, citalopram

Noradrenaline/SNRIs

Venlafaxine, duloxetine, milnacipran

Others

Bupropion

Anti-epileptics

Gabapentin, pregabalin, carbamazepine, oxcarbazepine, lamotrigine,

topiramate, tiagabine, levetiracetam, zonisamide, phenytoin, valproic acid

Multipurpose analgesics

Corticosteroids

Dexamethasone, prednisone

Multipurpose analgesics

2 adrenergic agonists

Clonidine, tizanidine

Multipurpose analgesics

NMDA receptor antagonists

Ketamine, dextromethorphan, memantine, amantadine

Neuropathic pain

GABA agonists

Baclofen

Musculoskeletal pain

Local anesthetics

Lidocaine, mexiletine

Neuropathic pain

Topical analgesics

Capsaicin, lidocaine, lidocaine/prilocaine (EMLA)

Neuropathic pain

Benzodiazepines

Diazepam, lorazepam, clonazepam

Musculoskeletal pain

Conotoxins

Ziconotide

Neuropathic pain

Muscle relaxants

Cyclobenzaprine, carisoprodol, methocarbamol, metaxalone, orphenadrine Musculoskeletal pain

Neuroleptics

Olanzapine

Bisphosphonates

Pamidronate, zoledronic acid, clodronate

RANKL inhibitor

Denosumab

Bone pain

Other adjuvant analgesics

Psychostimulants

Methylphenidate, modafinil

Anticholinergics

Hyoscine, glycopyrrolate

Calcitonin
Radiopharmaceuticals
Octreotide

Strontium89, samarium153A

Cannabinoids
Table adapted from Lussier et al. (2); Abbreviations: TACs, tricyclic antidepressants; SSRIs, selective serotonin reuptake inhibitors;
SNRIs, serotonin reuptake inhibitors; NMDA, N-methyl D-aspartate; GABA, gamma amino butyric acid; RANKL, receptor activator of nuclear
factor kappa B ligand.

octreotide (2,3). These groups of drugs, along with examples

of individual drugs that could be used as adjuvant analgesics,
are summarized in Table 1. Table 2 lists all the adjuvant
analgesics approved by Food and Drug Administration
(FDA) for the indication of pain. This chapter discussion
will focus on the classes of drugs most commonly used and
studied for adjuvant analgesia.
Antidepressants
Many antidepressants have well-established analgesic effects
independent of antidepressant effects. Efficacy as an antianalgesic does not correlate with antidepressant efficacy.

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Various agents from the antidepressant class of drugs

have been used for analgesia in chronic pain syndromes,
for example, fibromyalgia, neuropathic pain and cancer
pain. Antidepressants are less helpful for most acute
musculoskeletal pain. They have the additional advantage
of treating anxiety and insomnia along with depression.
Antidepressants that work by increasing norepinephrine
have better pain relieving capabilities than those which
increase serotonin. This is likely why the selective
serotonin reuptake inhibitors (SSRIs) have not been shown
to be effective for pain, even though they are effective
antidepressant drugs. Mechanisms of action of groups of
antidepressants are explained in Table 3. At the time of

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Table 2 List of adjuvants with FDA approval for pain management

Adjuvant analgesic

FDA approved pain indication

Duloxetine

Neuropathic pain associated with diabetic peripheral neuropathy; fibromyalgia

Milnacipran

Fibromyalgia

Gabapentin

Neuropathic pain associated with post herpetic neuralgia

Pregabalin

Neuropathic pain associated with diabetic peripheral neuropathy and post herpetic neuralgia; fibromyalgia.

Carbamazepine

Neuropathic pain, trigeminal neuralgia, glossopharyngeal neuralgia

Bupivacaine liposome
(injectable suspension)

Post-operative pain

Ropinirole

Pain associated with restless leg syndrome

Pramiprexole

Pain associated with restless leg syndrome

Migraine prophylaxis

Topiramate, divalproex

Ziconotide

Severe chronic pain in patients who are intolerant or refractory to all other available treatment including systemic
analgesics, adjunctive therapies, intrathecal opiates

Table 3 Mechanism of action of each group of antidepressants

Mechanism of action
MAO reuptake inhibition
Receptor antagonism

Site of action

SNRI

Bupropion

TCA

SSRI

Serotonin

Noradrenaline

Adrenergic (alpha-1)
NMDA

+ (milnacipran)

nAChR
Block/activate Ion channel

Na+ channel blocker

+ (venlafaxine)

+ (fluoxetine)

Ca2+ channel blocker

(duloxetine)

+ (citalopram, fluoxetine)

K+ channel blocker

Nicotinic receptor channel

Adenosine

adenosine availability and

local release; activation of
adenosine A1 receptor

+ (amitriptyline)

GABA B receptor

GABA B receptor function

+ (amitriptyline,
desipramine)

+ (fluoxetine)

Opioid receptor binding/

opioid-mediated effect

Activation of and opioid

receptors

+ (venlafaxine)

+ (paroxetine)

Inflammation

PGE2 production

+ (fluoxetine)

TNF production

Abbreviations: SNRI, serotonin and norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant; SSRI, selective serotonin reuptake
inhibitor; MAO, monoamine oxidase; NMDA, N-methyl D-aspartate; GABA, gamma amino butyric acid; nAChR, acetylcholine nicotinic
receptors; PGE, prostaglandin E; TNF, tumor necrosis factor. Adapted with permission from Dharmshaktu et al. (4).

discontinuation of an antidepressant, care should be taken

to slowly taper the medication in order to avoid withdrawal
syndromes (5). Direct comparison of the analgesic efficacy
of various antidepressant drugs has not been explored in
many studies. Table 4 describes adverse effects and drug
interactions of antidepressants commonly used for pain

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management, while Table 5 shows initial dose and usual

effective dose of antidepressants used for pain management.
Serotonin noradrenaline reuptake inhibitors (SNRIs)
SNRIs, such as duloxetine and venlafaxine, have been shown

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Table 4 Common adverse effects and drug interactions of antidepressants

Drug/drug
class

Adverse effects

Precautions

Potential drug interactions

Venlafaxine

Nausea, somnolence, hypertension,

dry mouth, constipation, sexual
dysfunction, blood dyscrasias,
hyponatremia, SIADH

Caution in hypertension or seizure MAOIs, TCAs, SSRIs, pimozide, tramadol,

disorders, suicidal behavior, renal or triptans, erythromycin, haloperidol, linezolid,
liver disease, pregnancy (especially trazodone, duloxetine, pseudoephedrine
in third trimester)

Bupropion

Tachycardia, insomnia, agitation,

tremor, dry mouth, headache,
constipation, Stevens-Johnson
syndrome

Contraindicated in seizure history,

caution in suicidal behavior, renal
and liver disease

MAOIs, SSRIs, beta-blockers, tramadol,

warfarin, levodopa, pseudoephedrine

Duloxetine

Nausea, dry mouth, constipation,

somnolence, insomnia, dizziness,
sweating, fatigue, decreased appetite

Caution in hypertension and seizure

disorders, suicidal behavior, renal
and liver disease, pregnancy
(especially in third trimester)

MAOIs, phenothiazines, amiodarone, betablockers, haloperidol, ritonavir, quinolones,

TCAs, SSRIs, triptans, tramadol, propoxyphene,
bupropion, venlafaxine, pseudoephedrine

Milnacipran Nausea/vomiting, headache,

Caution in ESRD, liver disease,
constipation, insomnia, dizziness,
alcohol abuse, glaucoma
palpitations, hyperhidrosis,
hypertension, dry mouth, urinary
retention, seizures, serotonin syndrome

MAOIs, triptans, venlafaxine, digosin,

duloxetine, olanzapine, fluosxetine,
sibutramine, SSRI

TCAs

Sedation, confusion, orthostatic

hypotension, weight gain, tachycardia,
arrhythmia, anticholinergic effects
(dry mouth, blurred vision, urinary
retention, constipation)

MAOIs, SSRIs, anticholinergic agents,

antiarrythmic, clonidine, lithium, tramadol,
linezolid, flumazenil, pimozide, carbamazepine,
carbonic anhydrase inhibitors, rifampins,
valproic acid, agents that prolong QTc interval

SSRIs

Nausea, headache, diarrhea, insomnia, Caution in seizure disorders,

dizziness, tremor, constipation,
suicidal behavior, pregnancy
sexual dysfunction, hponatremia, SIADH, priapism, platelet dysfunction

Caution in elderly, medically ill

cardiovascular disorders, seizure
history, narrow angle glaucoma,
suicidal behavior

MAOIs, other SSRIs, ergot alkaloids, pimozide,

TCAs, tramadol, aspirin, NSAIDs, buspirone,
trazodone, triptans, aspirin, NSAIDs, buspirone,
trazodone, triptans, linezolid, methylphenidate,
phenothiazines, propoxyphene, pheytoins

Abbreviations: MAOI, mono amine oxidase inhibitors; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants;
SIADH, syndrome of inappropriate antidiuretic hormone secretion; ESRD, end stage renal disease; NSAIDs, non-steroidal anti-inflammatory
drugs. Adapted with permission from McDonald and Portenoy (6).

to possess analgesic properties in various studies. Both these

drugs are devoid of anticholinergic and antihistamine effects
of the TCAs. Venlafaxine has been found to be effective
in painful polyneuropathy, diabetic neuropathy, and
neuropathic pain, following treatment of breast cancer (6).
It has potent serotonin reuptake inhibition, but weaker
norepinephrine reuptake effects. Both immediate and
sustained-release formulations of this drug are available,
and the drug is known to be well tolerated. A comparison
of venlafaxine and tricyclic antidepressants has shown both
drugs to possess analgesic properties, with venlafaxine having
comparable efficacy (4,7), but better toxicity profile (8).
The risk of gastrointestinal (GI) bleeding is significantly
increased when used simultaneously with non-steroidal
anti-inflammatory drugs (NSAIDs) (9). If concomitant use
of both these agents cannot be avoided, a GI prophylaxis

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agent should be considered (9). Venlafaxine use, particularly

in daily doses greater than 200 mg, is associated with doserelated hypertension and therefore, it is recommended that
patients undergo regular blood pressure monitoring (10).
Providers should avoid venlafaxine in patients with
uncontrolled hypertension, as well as in patients who are
at high risk of developing ventricular arrhythmia (10).
The cardiovascular side effects seen with venlafaxine are
more common in elderly patients. In a prospective cohort
study of elderly patients, 24% of initially normotensive
participants and 54% of those with preexisting hypertension
had an increase in blood pressure, whereas orthostatic
hypotension developed in 29% of the patients (10). A
significant increase in the QTc interval was also found
in some patients. Withdrawal symptoms may occur with
abrupt discontinuation of venlafaxine (6). Venlafaxine

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Table 5 Initial dose and usual effective dose of antidepressants for

pain control
Drug

Starting dose

Usual effective dose

Venlafaxine

5075 mg daily

75225 mg daily

Bupropion

100150 mg daily

150450 mg daily

Duloxetine

60 mg daily

60 mg daily

Milnacipran

25 mg daily

50100 mg daily

Amitriptyline

1025 mg nightly

50150 mg nightly

Nortriptyline

1025 mg nightly

50150 mg nightly

Desipramine

1025 mg nightly

50150 mg nightly

Paroxetine

1020 mg nightly

2040 mg nightly

Citalopram

1020 mg nightly

2040 mg nightly

TCAs

SSRIs

Abbreviations: TCAs, tricyclic antidepressants; SSRIs, selective

serotonin reuptake inhibitors. Adapted with permission from
McDonald and Portenoy (6).

is metabolized by CYP2D6 and patients with decreased

CYP2D6 expression tend to have more side effects with its
use (11). Despite a theoretical possibility of drug interaction
with agents that inhibit or stimulate CYP2D6, no such drug
interactions have been observed in clinical practice.
Desvenlafaxine is a salt form of the major active
metabolite of venlafaxine (12). The oral formulation has
quick and direct effects in neuronal systems of the brain.
Unlike venlafaxine, desvenlafaxine is not metabolized by
CYP450 enzymes and is associated with only minimal
inhibition of CYP enzymes, leading to low risk of drug
interactions and inter-individual pharmacokinetic variability
(12,13). Though it has been shown to be effective as an
antidepressant, there is little evidence that desvenlafaxine is
effective in management of pain syndromes (13). However,
it is utilized off-label by physicians in management of
neuropathic pain and fibromyalgia based on success of
venlafaxine in these conditions.
Duloxetine is another SNRI that is a potent dual reuptake
inhibitor of serotonin and norepinephrine. Randomized
controlled trials (RCTs) of duloxetine versus placebo have
shown relief in painful polyneuropathy. Duloxetine is also
found to have an activating action helpful in hypoactive,
depressed, or fatigued patients (2). Duloxetine was the first
antidepressant medication to be approved by FDA for the
treatment of neuropathic pain, specifically associated with
diabetic neuropathy (6). Common dose-limiting side effects
associated with duloxetine include nausea and somnolence.

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It should not be combined with agents like CYP 1A2

inhibitors or nonselective, irreversible monoamine oxidase
inhibitors (14). Clinical trials have shown the analgesic
efficacy of duloxetine for poly diabetic neuropathy and
fibromyalgia along with improvements in quality-of-life
measurements (15,16). Duloxetine is a frequently preferred
option in neuropathic pain management because it is
efficacious and well tolerated.
Milnacipran is the newest SNRI available that has a
strong selectivity for norepinephrine reuptake (5). Some
RCTs have shown milnacipran to be highly effective in
the treatment of fibromyalgia (17,18). When a systematic
review of RCTs was performed in fibromyalgia patients
receiving milnacipran 100200 mg daily, it was found to
be effective for only a minority of people for the treatment
of fibromyalgia pain, providing moderate levels of relief
when compared with placebo (19). Milnacipran is the only
antidepressant other than duloxetine that is FDA approved
for treatment of fibromyalgia pain. Milnacipran does not
undergo cytochrome P450 metabolism, and has a half-life
of 68 hours. Fifty-five percent of each dose is excreted
unchanged in the urine. Recently, a RCT concluded that
addition of milnacipran to pregabalin in fibromyalgia
patients who respond incompletely to the disorder showed
improved pain, global status and other symptoms (20).
Tricyclic and tetracyclic antidepressants (TCAs)
TCAs are comprised of tertiary amines (amitriptyline,
imipramine, clomipramine, doxepin) and secondary amines
(nortriptyline, desipramine), both of which have analgesic
properties. Secondary amines are generally better tolerated.
Maprotiline and mirtazapine are tetracyclic antidepressants.
Amitriptyline, nortriptyline, and desipramine inhibit both
serotonin and norepinephrine reuptake to varying degrees
and are effective for most neuropathic conditions. Their
action is mediated by multiple pathways, which include
increasing neurotransmitter availability in endogenous
monoamine-mediated pain-modulating brain pathways
that use serotonin or norepinephrine, interaction with
endogenous opioid systems, and pharmacokinetic
interactions with opiates leading to higher opiate
concentrations (6). Studies have shown that the dose of
TCAs required for analgesia frequently are lower than the
dose needed to manage depression, with a faster onset of
analgesic action in comparison to antidepressant action. A
provider should closely monitor patients when using TCAs
and limit use in the elderly, due to their relatively frequent

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and poorly tolerated anticholinergic side effects. A study

assessing the association between the use of antidepressants
and future risk of cardiovascular disease (CVD) showed that
TCAs are associated with a 35% increased risk for future
CVD, which is not explained by psychiatric illness (21).
Therefore, TCAs should be avoided in patients with CVD.
Tetracyclic antidepressants like maprotiline and
mirtazapine do not have strong evidence for use in pain
management. A randomized double-blind, placebocontrolled trial in non depressed patients concluded that
mirtazapine had better efficacy, in comparison to placebo,
in decreasing the duration, intensity and frequency of
chronic headaches when used as a prophylaxis (22). Another
uncontrolled study, with 594 patients, showed potential
beneficial effect of mirtazapine in the treatment of patients
with pain and concomitant depression (23). However, there
exists a need for placebo-controlled studies to confirm this
benefit.
An older study compared maprotiline with amitriptyline,
revealing that there was no significant difference between
the two drugs in the treatment of painful neuropathy in
diabetics and non-diabetics (24). Another study evaluated
the effect of long term administration of maprotiline
on sensory nerve function in patients with post herpetic
neuralgia (PHN) via measurement of current perception
thresholds (CPTs). Maprotiline, 60 mg daily, increased
CPTs at two months in PHN patients when compared to
controls, correlating well with decrease in pain score (25).
Co administration of maprotiline has also been shown to
increase the anti-nociceptive duration of morphine fourfold (26).
Selective serotonin reuptake inhibitors (SSRIs)
Even though SSRIs possess potent antidepressant action,
their analgesic action has been shown to be relatively
ineffective. There are some positive RCTs of the
combination of paroxetine and citalopram being effective
for diabetic peripheral neuropathy (27-29). Some studies
of trazodone in cancer pain and fibromyalgia have shown
positive results (30,31), whereas it has not been shown to
be an effective analgesic in dysesthesic pain from traumatic
myelopathy and burning mouth pain (32,33). A recent trial
of trazodone in fibromyalgia showed that its combination
with pregabalin enhanced the degree of improvement in
the symptomatology associated with fibromyalgia, when
compared with trazodone when given alone (34). Data is
limited on the analgesic efficacy of other SSRIs.

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Other antidepressants
Bupropion is an antidepressant that inhibits serotonin,
norepinephrine, and less potently dopamine. It is prescribed
for smoking cessation and neuropathic pain (35,36). Isolated
case reports have shown that bupropion has analgesic action
in chronic headaches (37), but studies failed to show benefit
in treatment of non-neuropathic back pain (38). Similar to
duloxetine, bupropion is also activating. A major advantage
of bupropion over other antidepressants is its low risk of
somnolence and sexual dysfunction.
Antiepileptics
Antiepileptic agents have strong positive evidence in
randomized trials and have been successful in clinical
practice when used for neuropathic pain. Multiple
antiepileptics are available, including typical antiepileptics
(carbamazepine, oxcarbazepine, phenytoin and valproate)
and atypical antiepileptics (gabapentin, pregabalin,
topiramate, lamotrigine, and clonazepam). It is thought that
they work so well for the management of neuropathic pain
syndromes because of their ability to decrease the neuronal
excitability. The hyperexcitable state of neuropathic pain is
associated with reduced thresholds and ectopic discharges at
the spinal dorsal horn or dorsal root ganglion pain neurons
due to upregulation of sodium and calcium channels (39).
While carbamazepine, oxcarbazepine, phenytoin and
lamotrigine suppress the ectopic discharges by inhibition of
sodium channels, gabapentinoids act through modulation of
calcium channels (40).
Gabapentin and pregabalin, the gabapentinoids
antiepileptics, are both efficacious in treating neuropathic
pain. Unlike other anticonvulsants that have action at
GABA or sodium channels, they instead inhibit release of
nociceptive neurotransmitters, glutamate and substance
P, by reducing the calcium influx into presynaptic nerve
terminals. Gabapentin is considered as first-line treatment for
neuropathic pain syndromes, due to its favorable side effect
profile and no major drug interactions (41,42). Gabapentin
has been shown to be well tolerated and efficacious for the
treatment of neuropathic pain in multiple placebo-controlled,
randomized clinical trials (43-47). The drug is frequently used
for postherpetic neuralgia, painful diabetic neuropathy, and
cancer associated neuropathic pain. Addition of gabapentin
has also shown a synergistic effect in patients already receiving
opioids for cancer pain, where the combination is more
effective than either drug alone (48). Poor oral bioavailability

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and nonlinear pharmacokinetics with dose escalation are a few

limitations encountered with the use gabapentin, which makes
it difficult to predict appropriate therapeutic dose and requires
a prolonged titration time period.
Pregabalin, a drug structurally similar to gabapentin,
was developed to overcome the issues of low potency and
nonlinear pharmacokinetics encountered with gabapentin.
It is widely used in treatment of neuropathic pain when
gabapentin is not tolerated. As opposed to gabapentin, the
pregabalin dose may be more rapidly escalated. Pregabalin
is known to cause weight gain. Similar side effects have
been seen with its counterpart gabapentin (Table 6).
An actively transported prodrug of gabapentin, gabapentin
enacarbil, recently became available for treatment of restless
leg syndrome (RLS). An integrated retrospective analysis
of various doses of gabapentin enacarbil was performed to
compare their efficacy and side effects. The results showed
that gabapentin enacarbil 600 mg once daily significantly
improved RLS symptoms in comparison with placebo (49).
Lamotrigine has been shown to have efficacy in
neuropathic pain not related to cancer (50,51). Lamotrigine
works by blocking tetrodoxin-resistant sodium channels and
inhibition of glutamate release from presynaptic neurons.
It has been shown to improve pain associated with diabetic
neuropathy, multiple sclerosis, spinal cord injury, central
post stroke pain, polyneuropathy, complex regional pain
syndrome, and refractory trigeminal neuralgia (52). The side
effect profile is similar to other centrally acting analgesics
that require a slow titration of the drug. Important concerns
to monitor with lamotrigine, are the potential for rash
and Stevens-Johnson syndrome. Table 7 shows initial dose
and usual effective dose of anti epileptics used for pain
management.
Corticosteroids
Corticosteroids can provide pain relief in many cancer pain
syndromes, including bone pain associated with metastasis,
neuropathic pain from either spinal cord compression or
nerve infiltration by direct tumor infiltration, pain from
lymphedema or due to bowel obstruction, headache due
to increased intracranial pressure, and arthralgia (2). Their
analgesic action is mediated by the decrease in edema
around pain sensitive structures and potential decrease in
the ephaptic neural discharges (5). No studies of analgesic
effects have been performed, to date, about the relative
potency, efficacy and dose response relationship among
different corticosteroid agents. Providers often choose

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dexamethasone based on its theoretical advantage of

possessing low mineralocorticoid activity, but prednisone or
methylprednisolone can also be used (2). Dosing of steroid
can be done variably. Dexamethasone is usually effective in a
low dose regimen (at a dose of 212 mg daily) for achieving
analgesia. Short term use of high-dose steroids is mainly
recommended for patients whose have rapidly increasing pain
along with functional impairment (3). Particular attention
should be given to the risk of side effects like GI bleeding,
severe dyspepsia and candidiasis. They should be avoided
in patients who have delirium, infection, and uncontrolled
glucose levels. In circumstances where a trial of corticosteroid
therapy is not effective, it is reasonable to taper it off.
Bisphosphonates, denosumab and calcitonin
Bisphosphonates were originally used to treat
hypercalcemia associated with cancer. Incidentally, they
also were found to have analgesic effects on pain of bony
origin. They are found to be efficacious particularly with
bone metastasis (53), and multiple myeloma (54,55). The
available bisphosphonate agents that have shown efficacy
in malignant bone pain conditions are zoledronate and
pamidronate. Zoledronic acid is the most commonly
used, as it has shown superiority in comparison to other
bisphosphonates in management of skeletal related events
(56,57). Denosumab is a novel human monoclonal antibody
that inhibits bone resorption by binding to the receptor
activator of nuclear factor kappa B ligand (RANKL). It
is indicated for prevention of skeletal-related events in
patients with solid tumor metastasis and helps in relief of
bone pain (58-60). A recent systematic review of multiple
RCTs showed that denosumab is more effective than
zoledronic acid for bone pain interference and prevention
of progression of bone pain severity (60).
Calcitonin has been found to be effective in treating
bone pain associated with acute osteoporotic fractures, but
not in chronic fractures (61-63). It has weak evidence in
treatment of bone pain in cancer patients (64). Studies of
calcitonin in treating neurogenic claudication from lumbar
canal stenosis have shown negative results (65,66). It can
be administered as intranasal spray, per rectal formulation,
subcutaneous and intravenous injection. The most common
side effects include nausea and skin hypersensitivity.
Alpha-2 adrenergic agonists
In the past, alpha-2-adrenergic agents were used primarily

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Somnolence, dizziness, ataxia, diplopia, headache,

confusion, nausea and depression, Stevens-Johnson
syndrome/severe rash (black box warning), bone
marrow suppression, pancreatitis and hepatotoxicity

Somnolence, dizziness, ataxia, anxiety, speech

disturbances, psychomotor slowing, abnormal vision,
memory difficulty, paresthesia and diplopia, pancreatitis, hepatotoxicity, nephrolithiasis, osteomalacia,
osteoporosis, hyperthermia, anemia, leukopenia,
psychosis

Dizziness, somnolence, diplopia, fatigue, nausea,

vomiting, ataxia, abnormal vision, abdominal pain,
tremor, dyspepsia, angioedema, leukopenia, Stevens-johnsons syndrome, hyponatremia, increased
liver enzymes

Dizziness, asthenia, somnolence, nausea,

nervousness, irritability, tremor, abdominal pain,
difficulty with concentration or attention, seizures (in
non-epileptic patients), severe rash

Somnolence, headache, asthenia, infection, dizziness,

emotional lability, psychosis, suicide attempts,
leukopenia, neutropenia, pancytopenia,
thrombocytopenia

Somnolence, anorexia, dizziness, headache, nausea,

agitation, irritability

Lamotrigine

Topiramate

Oxcarbazepine

Tiagabine

Levetiracetam

Zonisamide

Adapted with permission from McDonald and Portenoy (6).

Dizziness, somnolence, peripheral edema, amblyopia,

dry mouth, ataxia headache, confusion, diarrhea

Pregabalin

Adverse effects

Somnolence, dizziness, ataxia, weight gain, peripheral

edema, dyspepsia, leukopenia

Gabapentin

Drug

Precautions

Potential drug interactions

Rifampins, carbamazepine, ethosuximide, oxcarbazepine,

phenobarbital, phenytoins, ethanol, lopinavir, ritonavir,
pimozide, pyimethamine/sulfadoxine, trimethoprim,
sulphamethoxazole

May potentiate opioids, ethanol, benzodiazepines

Antacids, naproxen, may potentiate opioids, ethanol

Ethanol, ethosuximide, pimozide, carbamazepine, phenytoin, phenobarbital

Amlodipine, atorvastatin, calcium channel blockers, oral

contraceptives, clarithromycin, phenytoin, valproic acid,
carbamazepine, Phenobarbital

Avoid if allergic to sulpha,

discontinue at first sign of rash;
caution in renal and liver
disease, nephrolithiasis;
teratogenic

Phenytoin, valproic acid, carbamazepine, phenobarbital,

bosentan, CNS depressants, anticholinergics, diltiazepam,
metoclopramide, protease inhibitors, rifampin

Lower dose in patients with

None
renal disease and in the elderly; avoid
abrupt withdrawal;
caution in pregnancy

Lower dose in liver disease;

caution in non-epileptic
patients; teratogenic;
avoid abrupt withdrawal

Lower dose in patients with

renal disease; discontinue at
first sign of rash, teratogenic

Can cause metabolic acidosis, lower Carbonic anhydrase inhibitors, oral contraceptives,
dose in kidney and
phenytoin, valproic acid, carbamazepine, digoxin,
caution in liver disease;
metformin, lithium, amitriptyline, risperidone
teratogenic

Reduce dose with valproic acid, oral

contraceptives, or hepatic or renal
disease, discontinue at first sign of
rash; teratogenic

Lower doses in elderly and renal

insufficiency; caution in pregnancy

Lower doses in elderly and renal

insufficiency; caution in pregnancy

Table 6 Common adverse effects and potential drug interactions of antiepileptics

Page 8 of 14
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Page 9 of 14

Table 7 Initial dose and usual effective dose of anti-epileptics for

pain control
Drug

Starting dose

Usual effective dose

Gabapentin

100300 mg qhs

9003,600 mg
daily divided bidtid

Pregabalin

150 mg daily

150300 mg bid

Lamotrigine

2550 mg daily

200400 mg daily

Topiramate

25 mg daily

200400 mg daily

Oxcarbazepine

75150 mg bid

150800 mg bid

Tiagabine

4 mg qhs

4 mg tid

Levetiracetam

250500 mg bid

5001,500 mg bid

Zonisamide

100 mg daily

100200 mg bid

Adapted with permission from McDonald and Portenoy (6).

to treat hypertension, but their clinical use has now

expanded widely in anesthesia, peri-operative and postoperative pain control, sedation, anxiolysis and treatment
of chronic pain syndromes (67). Side effects include
hypotension, bradycardia and sedation. Clonidine,
tizanidine and the newer -2 adrenergic, dexmedetomidine,
are the most commonly used -2 adrenergic agents in
clinical practice. Both clonidine and dexmedetomidine
are selective agonists of -2 adrenergic receptors, with an
-2 to -1 ratio of 200:1 and 1,620:1, respectively (68,69).
Therefore, dexmedetomidine is approximately eight times
more specific than clonidine to -2 adrenergic receptors.
Studies of -2 adrenergic agents implicate that their
action are mainly central at the spinal-cord level (67), but
dexmedetomidine has both peripheral action and central
action.
Clonidine improves the analgesic efficacy of local
anesthetics and morphine, in addition to providing
postoperative analgesia. The evidence supporting the
postoperative analgesic effect is the strongest when clonidine
is used regionally, particularly as adjunct to peripheral nerve
and plexus blocks (70,71), and intrathecal anesthesia (72,73)
, with a possible efficacy with epidural route (74-76). Unlike
clonidine, dexmedetomidine is rarely given epidurally or
intrathecally, likely due to the possible neurotoxic effects
associated with epidural administration (77). Studies with
dexmedetomidine have shown that when it is given as a
single agent, there was a morphine-sparing effect, but no
improvement in pain scores (78-80). However, the studies
exploring postoperative analgesia of dexmedetomidine
are far fewer in number than clonidineimplicating that
analgesic benefit of dexmedetomidine in post-operative

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period needs to be further explored.

N-methyl-D-aspartate (NMDA) receptor
antagonists
Trials are ongoing, with numerous compounds that
specifically target mechanisms mediating neuropathic
pain involving the NMDA receptor. NMDA antagonists
have an interesting action of preventing sudden acute pain
from progressing into chronic pain by blocking receptors
of neurotransmitters that are essential for creating longterm pain pathways. NMDA antagonists also reduce opioid
tolerance and may enhance opioid analgesia. Their utility
is limited by significant dose-related, adverse effects,
including lightheadedness, dizziness, tiredness, headache,
bad dreams and sensory changes. Agents with clinically
relevant NMDA blocking properties include ketamine,
amantadine (an anti-influenza medication), memantine (an
Alzheimer dementia medication), dextromethorphan (an
anti-cough medication), and methadone (a mixed opioids
and NMDA receptor antagonist). Among these drugs,
ketamine and dextromethorphan remain the most studied
NMDA antagonists in the clinical setting for the treatment
of patients with neuropathic pain (81).
Ketamine is a strong NMDA antagonist that has been
used orally and intravenously for the treatment of chronic
regional pain syndrome (CRPS) and other neuropathic
pain conditions. Adverse effects seen with ketamine
include nausea, psychomimetic effects, intoxicated feeling,
headaches, hypertension and elevated liver enzymes (82). A
recently published systematic review of trials of ketamine
in refractory cancer pain confirmed it as a viable option
for this indication (83). A double-blind RCT of multi-day
low dose ketamine infusion as an adjuvant to gabapentin
in post-spinal cord injury related chronic pain confirmed
the safety and efficacy of this regimen (84). However, the
study also showed that the effects of low dose ketamine and
gabapentin ceased two weeks after infusion termination in
comparison to gabapentin in combination with placebo.
Some investigators have also explored the intranasal
formulation of ketamine, finding it promising for the
treatment of neuropathic pain (85).
Dextromethorphan, memantine and amantadine
are weaker NMDA receptor blockers, and therefore
have fewer CNS side effects. Dextromethorphan has
efficacy in treatment of neuropathic pain conditions, like
diabetic neuropathy, but not in post herpetic neuralgia
(86,87). A small cross over study showed that high dose

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Page 10 of 14

dextromethorphan, at 270 mg, provides analgesia in

patients with neuropathic pain post traumatic injury (88).
A multicentric clinical trial studied two fixed dose
combinations of dextromethorphan and quinidine
(45 mg/30 mg and 30 mg/30 mg, respectively) for diabetic
neuropathy leg pain and found both the doses to be
effective with acceptable tolerability profile (89). A welldesigned phase 3 trial found AVP-923 to have potential
for the treatment of diabetic neuropathy. AVP-923 is a
combination of two compounds, the active ingredient
dextromethorphan hydrobromide and the enzyme inhibitor
quinidine sulfate (a CYP450 2D6 inhibitor), which serves
to increase the bioavailability of dextromethorphan (90).
The use of this drug recently was approved for agitation in
patients with Alzheimers dementia, but not yet approved in
diabetic neuropathy.
Currently, memantine is marketed for the treatment of
dementia, and has been proposed as a medication for the
treatment of neuropathic pain for its mechanism, safety,
lack of serious adverse effects, and relatively rapid onset of
action (91). However, clinical trials have not been promising
and its routine use in neuropathic pain is not currently
recommended (91).
A novel drug, indantadol (V3381), which is an oral
NMDA antagonist and non-selective monoamine oxidase
inhibitor was being developed as a potential treatment of
neuropathic pain (92). Unfortunately, the phase II study
showed that it failed in treatment of neuropathic pain in
patients with diabetes.
-conotoxins
Ziconotide is a synthetic equivalent of -conotoxin, a
naturally occurring conopeptide (93,94). It is a N-type
calcium-channel blocker found in the conus magus, a
piscivorous marine snail. Intrathecal infusion of ziconotide
is approved by FDA for the treatment of severe chronic
pain in patients who are intolerant or refractory to other
treatments (95). At this time, clinical evidence to support
the use of ziconotide is limited. Ziconotide use is commonly
associated with side effects like confusion, dizziness, nausea,
nystagmus and contraindicated in patients with psychosis.
Summary
There are numerous pharmacotherapeutic options for the
management of chronic pain. Proper evaluation, along
with complete assessment of pain, is crucial to provide best

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Public Health and Emergency, 2016

possible analgesic approach. Optimization of analgesia in

the long-term setting requires achieving a proper balance
among efficacy, adverse effects, cost and other factors.
Primary treatment directed at the specific etiology of pain
is an important part of strategy to address poorly controlled
chronic pain. In order to optimize the balance between pain
control and toxicities, it is best to start the treatment with
an adjuvant analgesic after opioids have been used and their
doses well titrated.
Other than the introduction of an adjuvant analgesic,
other approaches to additional pain control include rotation
to an alternative opioid, trial of neuraxial infusion, and
non-pharmacological therapies (conservative such as use
of an orthotic or interventional such as neural blockade).
Antidepressants and antiepileptics are the two most
important categories of drugs with current widespread
clinical use for neuropathic pain management. No head to
head comparison of antidepressants and anticonvulsants
has been done in clinical trials for pain control, making it
difficult to recommend one class over the other as first-line
treatment. A provider may choose one class of drug over the
other because of certain comorbidities and other non-pain
symptoms. For example, patients with pain and concomitant
depression may benefit from antidepressants and those with
concomitant insomnia may benefit from sedating drugs.
Drugs with known relatively higher toxicities should be
started at a low dose and should be dose titrated as patients
become tolerant to side effects. If an adjuvant analgesic
produces a significant but incomplete analgesia, with side
effects that are tolerable, it should be continued with
consideration of addition of another adjuvant analgesic. The
first step in a comprehensive pain assessment should be to
determine the type of pain, then to get it under control as
soon as possible, with opioids if needed. The providers next
thought should be to add an adjuvant analgesic.
Acknowledgements
None.
Footnote
Conflicts of Interest: This article has been originally published
in the book The Art and Science of Palliative Medicine.
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doi: 10.21037/phe.2016.06.14
Cite this article as: Gupta N, Case AA. Adjuvant analgesics.
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