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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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Example
Antidepressants
TCAs
SSRIs
Paroxetine, citalopram
Noradrenaline/SNRIs
Others
Bupropion
Anti-epileptics
Multipurpose analgesics
Corticosteroids
Dexamethasone, prednisone
Multipurpose analgesics
2 adrenergic agonists
Clonidine, tizanidine
Multipurpose analgesics
Neuropathic pain
GABA agonists
Baclofen
Musculoskeletal pain
Local anesthetics
Lidocaine, mexiletine
Neuropathic pain
Topical analgesics
Neuropathic pain
Benzodiazepines
Musculoskeletal pain
Conotoxins
Ziconotide
Neuropathic pain
Muscle relaxants
Neuroleptics
Olanzapine
Bisphosphonates
RANKL inhibitor
Denosumab
Bone pain
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.
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Duloxetine
Milnacipran
Fibromyalgia
Gabapentin
Pregabalin
Neuropathic pain associated with diabetic peripheral neuropathy and post herpetic neuralgia; fibromyalgia.
Carbamazepine
Bupivacaine liposome
(injectable suspension)
Post-operative pain
Ropinirole
Pramiprexole
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
Site of action
SNRI
Bupropion
TCA
SSRI
Serotonin
Noradrenaline
Adrenergic (alpha-1)
NMDA
+ (milnacipran)
nAChR
Block/activate Ion channel
+ (venlafaxine)
+ (fluoxetine)
(duloxetine)
+ (citalopram, fluoxetine)
K+ channel blocker
Adenosine
+ (amitriptyline)
GABA B receptor
+ (amitriptyline,
desipramine)
+ (fluoxetine)
+ (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).
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Adverse effects
Precautions
Venlafaxine
Bupropion
Duloxetine
TCAs
SSRIs
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).
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Starting 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
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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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Lamotrigine
Topiramate
Oxcarbazepine
Tiagabine
Levetiracetam
Zonisamide
Pregabalin
Adverse effects
Gabapentin
Drug
Precautions
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
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Public Health and Emergency, 2016
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Starting 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
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doi: 10.21037/phe.2016.06.14
Cite this article as: Gupta N, Case AA. Adjuvant analgesics.
Public Health Emerg 2016;1:13.
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