PHARMACOLOGY

Non-opioid analgesics Learning Objectives

Bharti Seth After reading this article, you should be able to:
C correlate the pain pathway with the therapeutic targets for
analgesia
Abstract C state a broad classification for non-opioid analgesics
The International Association for the Study of Pain defines pain as ‘an C describe the concept of multi-modal analgesia
unpleasant sensory and emotional experience associated with actual
or potential tissue damage or described in such terms of such dam-
age’. This definition of the pain experience thus combines both the Transduction
phenomenon of nociception (the sensory nervous system’s response Begins when peripheral terminals of nociceptive C-fibres and
to certain harmful or potentially harmful stimuli) and pain perception A-delta (Ad) fibres are depolarized by noxious mechanical,
(process by which pain is recognized and interpreted by the brain). thermal or chemical energy. The membranes of these terminals
The Encyclopaedia Britannica defines an analgesic as any drug that contain proteins and voltage-gated ion channels that convert
relieves pains electively without blocking the conduction of nerve im- thermal, mechanical or chemical energy into an action potential
pulses, markedly altering sensory perceptions, or affecting conscious- (AP). Normally, nociceptor terminals have a high activation
ness. This selectivity is an important distinction between an threshold. However, nociceptors can be made more sensitive to
anaesthetic and an analgesic drug. Analgesics can thus be broadly stimuli. Injury to surrounding tissues (inflammation) or neurons
classified according to their role primarily on nociception as well as expose neighbouring nociceptors to irritating substances,
pain perception, both of which are intimately integrated to the pain including neurotransmitters, ATP, prostanoids, bradykinin, se-
experience. An understanding of the pain pathway is inherent to a rotonin, histamine, hydrogen ions (acid pH), and so on. These
good understanding of how therapeutic targets can act as analgesics. substances lower the nociceptor’s activation threshold. This is
An overview of this is discussed in this article to understand rationale called peripheral sensitization.
for therapeutic intervention. Opioids are substances that act on opioid Drugs acting at this phase include paracetamol and non-
receptors to produce morphine-like effects. Opioids have been used steroidal ant-inflammatory drugs (NSAIDs) by decreasing the
as a mainstay for pain management for centuries. As the problem of inflammatory mediators that cause a decrease in the generation
chronic pain has risen to epidemic proportions, so has the incidence of inflammatory mediators, and drugs acting on the transient
of increase in opioid use as well as misuse and abuse of prescription receptor potential vanilloid TRPV1 channel such as capsaicin.
opioids resulting in increasing morbidity and mortality. While being
effective for acute pain and cancer pain management, opioids have
not been very effective for the management of chronic pain or neuro- Transmission and modulation
pathic pain. All other analgesics that do not produce analgesia through Transmission of AP is from the peripheral terminals of the noci-
a primary effect on opioid receptors can be labelled as non-opioid an- ceptors to the central terminals of the nociceptive fibres in the
algesics (NOA). This article will aim to provide an overview of the pain dorsal horn of the spinal cord. The dorsal horn is organized into
pathway in relation to the therapeutic targets for providing analgesia, ten different laminae. Nociceptive fibres primarily terminate in
commonly used NAOs and their brief introduction. laminae I and II. The AP causes the presynaptic terminals of Að
Keywords Atypical analgesics; cannabinoids; COX-2 inhibitors; and C-fibres to release a variety of pro-nociceptive substances into
gabapentinoids; non-opioid analgesics; NSAIDs; paracetamol; topical the synaptic cleft, including glutamate which activates post-
analgesics synaptic a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
(AMPA) receptors, substance P (SP), which activates postsynaptic
Royal College of Anaesthetists CPD Matrix: 1A02 NK1 receptors and calcitonin gene-related peptide (CGRP), which
activates postsynaptic CGRP receptors. Glutamate can also acti-
vate N-methyl-D-aspartic acid (NMDA) receptors that are normally
inactive because they are ordinarily blocked by magnesium ions.
However, intense or prolonged periods of depolarization can
The pain pathway in relation to therapeutic targets
release the magnesium ion from the NMDA-linked channel. Loss
The pain pathway can be considered in terms of transduction, of the Mg blockade allows an influx of calcium ions. Increased
transmission, modulation and perception for purposes of un- intracellular calcium ions has two important effects, the first effect
derstanding the mechanistic basis of analgesics. The interven- leads to a lowered activation threshold and the second effect
tional therapies for pain management are aimed towards initiates a cascade that results in the production and release
interrupting or modulating the nociceptive pathways, and the of nitric oxide into the synaptic cleft. Presence of nitric oxide in
pharmacology of analgesic drugs is geared towards modulating the synaptic cleft causes an exaggerated release of neurotrans-
the biochemical processes involved. mitters from the presynaptic terminal resulting in synaptic hyper-
excitability. The NMDA receptor is considered critical for the in-
duction and maintenance of neuropathic pain.
Bharti Seth MD is a Consultant in Anaesthesia and Pain Medicine at The postsynaptic fibres transmit the pain sensation through
The Queen Elizabeth Hospital NHS Foundation Trust, King’s Lynn, second order neurons and interneurons to the central nervous
Norfolk, UK. Conflicts of interest: none declared. system via the spinothalamic (anterior and lateral) tracts.

ANAESTHESIA AND INTENSIVE CARE MEDICINE 20:8 456 Crown Copyright Ó 2019 Published by Elsevier Ltd. All rights reserved.
 PHARMACOLOGY

The dorsal horn of the spinal cord acts as the interface be- agent. It is the drug of choice in patients in whom NSAIDs are
tween the peripheral and central nervous system components of contraindicated.
the pain pathway. The mechanism of action of paracetamol is poorly under-
Modulation of the action potential (AP) can be peripheral as is stood. It has been postulated to affect both peripheral (inhibition
seen with: of cyclo-oxygenase [COX] activity) and central (COX, descending

inhibiting sensitization of nociceptive terminals as with serotonergic pathways, L-arginine/NO pathway, cannabinoid
cyclo-oxygenase inhibitors, e.g. NSAIDs system) antinociceptive processes.

inhibiting depolarization and repolarization of the axonal It shares analgesic and antipyretic properties with NSAIDs but
membrane, e.g. local anaesthetics does not possess any anti-inflammatory activity. Due to this, it is

inhibiting the inflammatory response to trauma, e.g. not considered a member of the NSAIDs family.
steroids. It is available in oral, rectal and intravenous formulations.
Central modulation of nociception begins at the dorsal horn of Oral paracetamol is well absorbed from the gut, subject to min-
the spinal cord and may be modulated through a multitude of imal first pass metabolism with a high though variable
receptors on primary afferent, descending nerves and in- bioavailability. Metabolized in the liver by the cytochrome P450
terneurons. Drugs that produce analgesia through activity at this enzyme system, it is generally safe and efficient. However,
level include alpha 2-agonists (clonidine), NMDA antagonists fulminant hepatic failure has been noted with iatrogenic over-
(ketamine), opioids and ziconotide. Central modulation also af- dose. Paracetamol dose reduction is advocated in certain patient
fects through descending pathways from brainstem structures to groups, including the elderly, infants, in starvation or malab-
the dorsal horn. Noradrenergic, serotonergic and opioid systems sorption, severe renal impairment, or hepatic failure where
all have an inhibitory effect. glutathione stores may be low. Glutathione conjugates with

Antidepressants enhance the analgesic activity of the NAPQI (N-acetyl-p-benzo-quinone-imine), a highly toxic metab-
descending pathway by increasing the availability of syn- olite of paracetamol. The use in children requires care and
aptic monoamines. The monoamines serotonin and dosage modification according to age as the CYP2E1 enzyme
norepinephrine are the primary neurotransmitters released required for the oxidation of paracetamol metabolism reaches
by descending pathway neuron terminals. adult levels only by 10 years of age.

Stimulation of the nucleus raphe magnus in the brainstem
results in antinociception attributed to the release of se- NSAIDs, cyclo-oxygenase-2 inhibitors
rotonin (5-HT) within the dorsal horn.
NSAIDs, including non-selective and selective COX-2 inhibitors

Stimulation of the locus coeruleus in the medulla results in
are widely used for their anti-inflammatory and analgesic effects.
antinociception attributed to the release of norepinephrine
They are an essential part of pain management because of the
within the dorsal horn. Pre-synaptically noradrenaline in-
central role of the COX pathway in generation of inflammation
creases inhibitory transmitters from interneurons and de-
and biochemical recognition of pain.
presses glutamate release from both Ad and C afferent
They are effective in a variety of disorders including rheu-
terminals.
matoid arthritis, osteoarthritis, ankylosing spondylitis, gout,
Perception headache disorders, dental pain and dysmenorrhea.
Of nociceptive pain is dependent upon neural processing in the The basic mode of action is inhibition of the pro-inflammatory
spinal cord and several brain regions. Pain becomes more than a enzyme COX. The COX enzyme exists in three isoforms: COX-1
pattern of nociceptive action potentials in the cerebral cortex. and COX-2, COX-3.
Action potentials ascending the spinothalamic tract are decoded COX-1 is expressed constitutively and in quiescent conditions;
by the thalamus, sensorimotor cortex, insular cortex and the it performs ongoing regulatory functions including gastro and
anterior cingulate to be perceived as an unpleasant sensation that renal protection, macrophage differentiation, platelet aggregation
can be localized to a specific region of the body. Action potentials and mucus production. It has a limited role in inflammatory
ascending the spinobulbar tract are decoded by the amygdala and process.
hypothalamus to generate a sense of urgency and intensity. It is COX-2 is an inducible enzyme that is unregulated by tissue
the integration of sensations, emotions and cognition that result injury and other stimuli including interleukin-1, tumor necrosis
in our perception of pain. This is how hypnosis, biofeedback, factor alpha (TNFa). It is active at injure sites and in a variety of
CBT and opioids work. tissues mediating inflammatory, pain, fever and carcinogenic
responses. It also has a regulatory role in reproduction, renal
Paracetamol physiology, bone resorption and neurotransmission.
The significance of COX-3 is uncertain. Because of the regu-
Paracetamol (acetaminophen) is the most commonly used anal- latory effects of these enzymes, their use is associated with sig-
gesic and has an impressive place on the WHO analgesic ladder. nificant side effects including gastric irritation and bleeding (15%
It is recommended on all three steps of pain treatment intensity. e30%) in patients taking nonselective NSAIDs, deranged renal
It is a useful first-line drug formula to moderate pain. For more autoregulation and impaired wound healing. Selective COX-2
persistent moderate to severe pain, when used in conjunction inhibitors while decreasing the gastric side effects are associ-
with other agents including NSAIDs (ibuprofen), caffeine, weak ated with greater incidence of cardiovascular adverse effects and
(codeine, tramadol) or strong (morphine) opioids, it improves are no longer recommended for long-term use or in patients with
analgesic efficacy while decreasing the side effects of the adjunct risk factors for such effects.

ANAESTHESIA AND INTENSIVE CARE MEDICINE 20:8 457 Crown Copyright Ó 2019 Published by Elsevier Ltd. All rights reserved.
 PHARMACOLOGY

As a group, NSAIDs are excellent analgesics and are more Anticonvulsants decrease ectopic neuronal activity and sta-
efficient than intramuscular morphine for purposes of acute pain bilize neuronal cell membranes through modulation of the
relief. Their use for chronic pain conditions, over long periods of voltage-gated sodium or calcium ion channels. These drugs may
time is not recommended and is associated with significant side inhibit sodium channels (phenytoin, lamotrigine and others) or
effects. inhibit calcium channels (gabapentinoids, that is, gabapentin and
pregabalin). The gabapentinoids have been recommended by
Antidepressants: tricyclic antidepressants (TCAs), NICE for use in neuropathic pain conditions including post
selective serotonin reuptake inhibitors (SSRIs) amputation pain. Levetiracetam is a novel anticonvulsant agent
which appears to exert a synergistic antihyperalgesic effect
TCAs are considered as first-line analgesics for neuropathic pain.
against inflammatory pain when combined with a non-steroidal
Their analgesic effects starts more rapidly and at lower doses than
anti-inflammatory drug (NSAID) plus caffeine.
required for the antidepressant effects. The primary mechanism
of action of tricyclic antidepressants (TCAs) is through blockade
Carbamazepine, which acts as a sodium channel blocker is the
of noradrenaline (NA) and serotonin (5-HT) at the dorsal horn
first line treatment for trigeminal neuralgia as recommended by
synapses. TCAs are considered NA and 5-HT re-uptake inhibitors,
NICE.
resulting in increased bioavailability of NA and 5-HT at the syn-
aptic terminals. Both NA and 5-HT modulate the dual descending
Topiramate, lamotrigine and valproate are anticonvulsants that
pain pathways in the body that inhibit pain signals.
are effective in the treatment of episodic migraine and neuro-
One pain pathway originates at midbrain level in the peri-
pathic pain. Adverse events associated with anticonvulsant
aqueductal gray and nucleus raphe magnus (5-HT), while the
agents are common and may be treatment-limiting. Some of the
other pain pathway starts at the locus coeruleus in the medulla
most frequently reported adverse events include drowsiness,
(NA).
headache, and increased appetite. Teratogenicity is another sig-
The mechanisms of analgesic effects of TCAs are extensive
nificant side effect.
and the following are postulated:

monoamine re-uptake inhibition
Novel topical agents: TRPV1 antagonists, 5% lidocaine

interactions with endogenous opioids
patches

NMDA receptor antagonism

immune factor expression modulation Capsaicin: TRPV1 is expressed in all sensory ganglia (dorsal

enhancement of gamma-aminobutyric acid beta (GABAB) root ganglia, trigeminal ganglia, vagal) and in small sensory
receptor activity C-and Ad fibres, which may contain various neuropeptides

blockade of sodium and potassium channels including SP and CGRP. It is activated by capsaicin, noxious

histamine inhibition heat (>43 C) and low pH. TRPV1 channel activation in noci-

adenosine system involvement. ceptive neurons triggers the release of neuropeptides and
They are also useful in multi-mechanistic chronic pain with a transmitters resulting in depolarization. After the depolariza-
neuropathic component and as adjuvant analgesics in nocicep- tion, the afferent nerve is in a refractory state, hence unable to
tive and inflammatory pain. Examples of TCAs include amitrip- transmit additional signals. Antagonists of TRPV1 provide
tyline, nortriptyline. analgesia by increasing the depolarization threshold required to
generate an action potential. Capsaicin is used the management
Duloxetine (a serotoninenorepinephrine reuptake inhibitor) is of inflammatory pain. Topical capsaicin in humans is rapidly
effective in treating painful diabetic peripheral neuropathy. and well absorbed through the skin and many low concentra-
tions of capsaicin (0.025e0.1%) are available over the counter
Venlafaxine blocks reuptake of noradrenaline and 5-HT and is as creams or patches (8%). It should not be applied to broken
relatively free of muscarinic cholinergic, histaminic, and alpha- skin.
adrenergic receptor activity. Its analgesic action is postulated
to involve the endogenous opioid system. It has been suc- Lidocaine patches (5%) are an option for superficial, localized
cessfully used for management of painful neuropathy and painful neuropathic conditions such as post herpetic neuralgia.
headache control. Lidocaine acts through blockade of abnormally functioning
In general, TCAs are more effective than selective serotonin (sensitized) Nav 1.7 and Nav 1.8 Naþ channels in dermal noci-
reuptake inhibitors because of their nonselective effects. The ceptors, thereby reducing ectopic discharges. It also regulates T-
number needed to treat (NNT) for 50% relief of neuropathic pain cell activity and inhibits nitric oxide production, thereby
is 6.7 for SSRI therapy compared to 2.4 for TCAs. The side effects reducing inflammatory processes within the deep tissue, such as
include drowsiness, sexual dysfunction, weight gain, dry mouth, injured muscle, joints or constricted nerves.
constipation, blurred vision and prolongation of the QRS interval.
Cannabinoids
Anticonvulsants
Cannabis is a naturally occurring substance with many active
These drugs have been recommended by NICE (National Insti- compounds including tetra hydro cannabinol (THC), cannabi-
tute for Health and Care Excellence) for use in neuropathic pain noid (CBD) and cannabinol (CBL). The CBD receptors CB1 and
conditions including post herpetic neuralgia, post stroke pain, CB2, located extensively in the brain and peripheral tissues, are
post amputation pain and persistent pain after hip replacement. G-proteinecoupled receptors that are linked to the Gi/o system in

ANAESTHESIA AND INTENSIVE CARE MEDICINE 20:8 458 Crown Copyright Ó 2019 Published by Elsevier Ltd. All rights reserved.
 PHARMACOLOGY

the same manner as opioid receptors and result in a reduction in Botulinum A toxin (Botox)
afferent neuronal transmission.
Botulinum A toxin is produced by Clostridium botulinum. It acts
Nabiximols (Sativex) is a sublingual spray containing the
irreversibly at the presynaptic membrane of the neuromuscular
combination of THC and CBD in a roughly 1:1 ratio. It is
junction, preventing release of acetylcholine and triggering
approved for use of multiple sclerosis related spasticity pain.
chemical denervation by inhibiting subsequent activation of
Dronabinol is a synthetic preparation of the transisomer of delta-
motor nerve endings, through destruction of SNARE (soluble
9-THC dissolved in sesame oil. Along with nabilone, it is used for
NSF attachment protein receptors) proteins. The effect disap-
chemotherapy-related nausea and as an appetite stimulant for
pears as collateral form in neuromuscular junction plates on new
HIV wasting syndrome.
areas of muscle cells. Botox is recommended by NICE for man-
Risk of psychological harm, addiction and dependence are
agement of chronic migraine when conservative therapy is not
present. It is still not available for routine prescription of pain
successful. It has not been found to be very effective for myo-
management in the NHS.
fascial trigger point injection therapy. Common side effects are
The current public opinion is moving toward more wide-
flu-like symptoms, pain, unintended paralysis of neighbouring
spread acceptance despite the continuing regulatory limbo in
muscles and erythema.
which the drug resides. Physicians will increasingly be encoun-
tering the use of cannabinoids in their practice whether or not
Multimodal analgesia
they choose to recommend medicinal cannabis or prescribe
cannabis-derived pharmaceuticals. Multimodal analgesia or ‘balanced analgesia’ combines analge-
sics from two or more drug classes or analgesic techniques that
Muscle relaxants employ different mechanisms of action, targeting different (pe-
ripheral or central) pain pathways, thus achieving a synergistic
These are usually prescribed to help treat myalgia and muscu-
effect at lower analgesic doses. Non-opioid analgesics form a key
loskeletal conditions, including chronic low back pain. This
component of fast track surgery and enhanced recovery by
group of drugs are broadly divided into antispastic agents and
minimizing side effects associated with traditional opioids used
antispasmodic agents. Antispastics act on the level of spinal cord
in high doses.
or skeletal muscles to decrease muscle hypertonicity and relieve
involuntary spasms. Antispastic agents (e.g. baclofen) are often
Summary
prescribed for patients with spinal cord injury, cerebral palsy and
multiple sclerosis. Analgesic therapy should be based on the patient’s pain
mechanisms. Non-opioid analgesics play an integral role in
Antispasmodics decrease muscle spasm by affecting conduction providing multimodal analgesia through therapeutic targets
through the central nervous system. Muscle relaxants may be along different parts of the pain pathway. They offer safer al-
helpful in the short-term setting for relieving a flare up of muscle ternatives to opioid analgesia for inflammatory, postoperative
spasms. and neuropathic pain. A

Benzodiazepines act by enhancing the effect of the neurotrans-

FURTHER READING
mitter gamma-aminobutyric acid (GABA) at the GABAA receptor.
IUPHAR/BPS guide to pharmacology. Jan 2018, http://www.
Non-benzodiazepine antispasmodics act at the level of the
guidetopharmacology.org.
brainstem and spinal cord and are frequently prescribed for flare
Rang and Dale’s pharmacology. 7th edn. Edinburgh: Elsevier Churchill
up of chronic painful conditions such as low back pain. These
Livingstone, 2011.
include methocarbamol, carisprodol and cyclobenzaparine.
Common side effects include sedation, headaches, visual dis-
turbances, drowsiness, fatigue and dizziness.

ANAESTHESIA AND INTENSIVE CARE MEDICINE 20:8 459 Crown Copyright Ó 2019 Published by Elsevier Ltd. All rights reserved.