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Introduction
e pharmacological treatment of pain includes the use of not
only opioid, non-steroidal anti-inflammatory drugs, tricyclic
antidepressants and anticonvulsants. is chapter discusses
the application of other groups of active compounds that are
of benefit in the treatment of pain as well as the discomfort
which can attend pain treatment.
Methylphenidate
Methylphenidate is a piperidine derivative and a mild central
nervous system (CNS) stimulant. It is used, particularly in
cancer pain patients, to ameliorate opioid-induced somnolence,
augment the analgesic effects of opioids, treat depression and
improve cognitive function.
e use of methylphenidate in non-cancer pain is limited
because of development of tolerance after long-term
administration. ere is also a potential for psychosis, sleep
disturbance and cardiac toxicity.
Pharmacology
Mechanisms of action
Methylphenidate is thought to exert its effects by binding to
the brain dopamine transporters in the presynaptic membrane
and inhibiting dopamine re-uptake; this results in an increase
in dopamine concentration in the synapse and surrounding
extracellular space.
Pharmaceutical preparations
e currently available preparations of methylphenidate
contain a racemic mixture of dl-threo-methylphenidate. ere
is a standard and a sustained-release formulation.
Other Medications and Adjuvants in
Pain Management
24
Anne Miu Han CHAN
INTRODUCTION
METHYLPHENIDATE
BENZODIAZEPINES
BOTULINUM TOXIN
BACLOFEN
KETAMINE
SYSTEMIC LOCAL ANAESTHETIC
TYPE DRUGS
CORTICOSTEROIDS
CANNABINOIDS
CLONIDINE
BISPHOSPHONATES
TOPICAL CAPSAICIN
OTHER DRUGS —
ANTIHISTAMINES
REFERENCES
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394 Anne Miu Han CHAN
Side eects
Common adverse effects reported in the literature
include anorexia, tachycardia, hypertension,
insomnia and nervousness. Methylphenidate has
abuse potential as it can induce euphoria, especially
when given intravenously [61].
Indications
Methylphenidate is used as adjuvant in patients
on opioids; it significantly reduces sedation and
potentiates the analgesic effect of the opioid.
Evidence-based material
e effect of combining psychostimulants and
analgesics to enhance analgesia has long been
recognised. Dextroamphetamine was first reported
more than 50 years ago to increase the pain threshold.
Forest et al. found that dextroamphetamine in
combination with morphine afforded greater pain
relief in a group of postoperative patients than the
same dose of morphine alone [24].
Benzodiazepines
Benzodiazepines are usually given to pain sufferers
in an attempt to diminish anxiety, excessive muscle
tension [39, 45, 46] and insomnia [4, 45, 46, 56].
In addition to their established effectiveness
for anxiety, insomnia and muscle spasm,
benzodiazepines can effect direct pain relief if anxiety
is responsible for an increase in the unpleasantness
of pain, muscle tension or increased sympathetic
outflow. Sleep disturbances and depression can
decrease tolerance for pain and increase pain-
related behaviour; patients thus affected may also
benefit from benzodiazepine treatment. Finally,
benzodiazepines can provide effective analgesia for
lancinating neuropathic pain syndromes, an effect
which may be related to the anticonvulsant action
of benzodiazepines. For example, in tic douloureux,
clonazepam (a benzodiazepine with anticonvulsant
properties) is used in patients who cannot tolerate
or do not respond to carbamazepine or baclofen
[1, 16].
Despite their widespread use in patients with chronic
pain, long-term therapy with benzodiazepines is
controversial due to the significant side effects.
Pharmacology
Mechanisms of action
e stimulation of benzodiazepine receptors affects
noradrenaline, serotonin, dopamine and gamma-
aminobutyric acid (GABA) neurotransmission
[34]. In animal studies, the analgesic effects and the
enhancement of the morphine effect of intrathecally
administered benzodiazepines appear to be mediated
by opioid, N-methyl-D-aspartate (NMDA) and, to
a lesser extent, benzodiazepine receptors [48, 54, 55,
79]. On the other hand, intracranially administered
benzodiazepines appeared not to have analgesic
effects; the abolished conditioned hypoalgesia
[35] and antagonised morphine antinociception
are possibly mediated through the activation of
GABA
A
and NMDA receptors [48]. Of relevance
is the finding that flumazenil, a benzodiazepine
receptor antagonist, appears to block preoperative
diazepam inhibition of morphine analgesia in
human dental pain [29]. Potential effects of long-
term benzodiazepine administration on serotonin
turnover and benzodiazepine receptor function are
a concern [34, 67].
Pharmaceutical preparations
Some commonly available benzodiazepine
preparations include diazepam (intravenous [IV]
and oral), midazolam (IV and oral), lorazepam (oral),
alprazolam (oral) and clonazepam (IV and oral).
Side eects
Physical dependency and withdrawal may occur
with prolonged administration (>6weeks) of
moderate to high dosage of a benzodiazepine. Such
problems are rare at usual therapeutic doses [49].
Daytime sedation, impaired co-ordination and
judgement, and other forms of cognitive disturbance
are common. ese adverse effects are more likely
if the patient is elderly or brain damaged, when
longer-acting benzodiazepines are used or if other
central depressant drugs are given at the same time
[15, 49].
Other reported adverse effects include depression,
suicidal thoughts, impulsivity and rebound
insomnia.
Indications
Benzodiazepines have been used in patients with a
wide range of pain conditions. ey are frequently
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Other Medications and Adjuvants in Pain Management
prescribed in combination with other analgesic
agents. Reported uses include neuropathic pain,
pain of musculoskeletal origin, such as tension
headache, temporomandibular joint disorder and
tic douloureux, and other heterogeneous conditions
such as fibromyalgia.
Evidenced based literature on
benzodiazepines
e evidence for any beneficial effect of
benzodiazepines in the treatment of neuropathic pain
is currently unsupported by controlled studies [19].
ere is evidence that the use of benzodiazepines
is helpful for certain chronic pain syndromes
such as tic douloureux, tension headache and
temporomandibular joint disorder. Even in these
conditions, however, the evidence of efficacy is scant
and the use of benzodiazepines should be restricted
to patients for whom established modalities have
failed to provide satisfactory results [19].
e available evidence on the efficacy of
benzodiazepines in treating acute lower back pain
is even less convincing [75].
Botulinum Toxin
Botulinum toxins are potent bacterial neurotoxins
produced by Clostridium botulinum. Botulinum
toxins are able to block acetylcholine release at
the neuromuscular junction to produce flaccid
paralysis. is results in a temporary (months)
chemodenervation and loss or reduction in activity
in the target organ (muscle, sweat gland, sphinters)
with minimal risk of systemic side effects.
Pharmacology
Mechanisms of action
Arrezzo described five possible mechanisms by
which botulinum toxin could directly or indirectly
alter pain [3]. ey include:
1. Changes in the sensitivity and response pattern
of group III and IV muscle nociceptors.
2. Diminished activity in the gamma-motor
neurons and consequent changes in muscle
spindle afferents.
3. Alterations in cholinergic control of vascular
and autonomic functions, including
neurogenic inflammation.
4. Inducement of neuroplastic changes in the
processing of afferent somatosensory activity
at multiple levels of the neuroaxis.
5. Direct non-cholinergic effects on pain
afferents.
Pharmaceutical preparations
ere are two types of commercially available
botulinum toxin A for clinical use: Botox
(botulinum type A purified neurotoxin complex,
Allergan, Inc., Irvine, CA) and Dysport (botulinum
toxin type A haemagglutinin complex, Ipsen Ltd,
Berkshire, UK) available in Europe.
Botulinum toxin B (Myobloc, Elan Pharmaceuticals
Inc., South San Francisco, CA) was approved by
the Food and Drug Administration in December
2000 for the treatment of cervical dystonia and is
presently in clinical trials for other conditions.
Type A seems to be most potent of the subtypes
[66] and when injected clinically has the longest
duration of action [64, 71]. Type B has hitherto
seen limited clinical use.
Side eects
Adverse effects include soreness at the site
of injection. Tsui et al. [73] reported on the
incidence of antibody formation in 32 patients
with spasmodic torticollis who received repeated
injections of botulinum toxin A. Existing guidelines
recommend keeping the dose as low as is necessary
(e.g. a maximum of 300 units of botulinum toxin
A) and injecting no more frequently than every 3
months. Difficulty in raising the head can occur
after botulinum toxin injection in the neck muscles
for treatment of headache.
Indications
In pain medicine, botulinium toxin has been used
in the treatment of involuntary muscle spasm and
tremors associated with dystonias (e.g. spasmodic
torticollis, blepharospasm, strabismus, limb
dystonia, paraspinal muscle spasm, thoracic outlet
syndrome).
It also appears to be a useful in refractory myofascial
pain syndrome and headache, most likely by
breaking the spasm or pain cycle and giving the
patient a “window of opportunity” for traditional
conservative measures such as physical exercises to
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396 Anne Miu Han CHAN
have a greater beneficial impact. It is an accepted
treatment in patients with refractory myofascial
pain and headache, who despite multidisciplinary
approaches continue to suffer [59].
Baclofen
Baclofen is a p-chlorophenyl derivative of gamma-
amino-butyric acid (GABA) and a skeletal muscle
relaxant.
Pharmacology
Mechanisms of action
e precise mechanism of action of baclofen is
not fully known. It inhibits monosynaptic and
polysynaptic reflexes at the spinal level, possibly
by acting as an inhibitory neurotransmitter and/or
by hyperpolarisation of afferent nerve terminals,
which in turn inhibits the release of excitatory
neurotransmitters such as glutamate and aspartic
acid. Baclofen may exert its effects by stimulation
of the GABA
B
receptor subtype.
Pharmaceutical preparations
Baclofen is available as 10 mg and 20 mg tablets.
ere is a parenteral formulation for intrathecal
injection containing 50 mcg/ml and intrathecal
refill kits of 10 mg/5 ml and, 10 mg/20 ml.
Side eects
e most common side effects are sedation and
confusion. Failure of a prolonged trial with baclofen
requires tapering the dose prior to discontinuation
because of its potential to precipitate withdrawal
symptoms. In large doses, baclofen may produce
generalised CNS depression including sedation,
ataxia, and respiratory and cardiovascular
depression.
Indications
Intrathecal baclofen has been used successfully to
treat spasticity, but the experience of its possible
effect on central pain in multiple sclerosis is unknown
[35]. It has also been used as adjunct treatment
in trigeminal neuralgia, pre-trigeminal neuralgia,
glossopharyngeal neuralgia, vagoglossopharyngeal
neuralgia, organic headache, neuropathic pain and
postherpetic neuralgia
Evidence-based material
Baclofen has previously been reported to have
efficacy in reducing pain in trigeminal neuralgia
[26]. e evidence for its use as an analgesic in
other conditions is weak.
Ketamine
Domino, Chidiff and Corssen reported the first
clinical use of ketamine more than 30 years ago
[21]. It was introduced as a less potent relative of
phencyclidine. Initially, it was used as a mono-
anaesthetic agent, but then its use as an anaesthetic
became selective due to its significant side effects.
A renaissance in the use of ketamine has occurred
as insight into its neuronal mechanism of action
as an anaesthetic and analgesic has accumulated
[2]. Ketamine has diverse effects which may be
of relevance to chronic pain, based on its effect
on NMDA, alpha-amino-3-hydroxy-5-methyl-
4-isoxazolepropionic acid (AMPA), kainate and
GABA receptors. Ketamine also inhibits voltage
gated Na+ and K+ channels, and serotonin and
dopamine re-uptake [38].
Clinically, ketamine is administered as a racemate
composed of two optical isomers, S(+) and R(-),
which exhibit some pharmacological differences.
Pharmacology
Mechanisms of action
Although NMDA receptors appear to represent the
primary target for its dissociative anaesthetic effect, a
myriad of interactions with other neurotransmitter
receptors and transporters, and voltage regulated ion
channels may underlie the complex constellation
of behavioural and anaesthetic actions of these
compounds [5, 30]. ese other sites of action
include non-NMDA glutamate receptors (AMPA
receptors, kainite receptors, mu, kappa and delta
opioid receptors and GABAA receptors). Other
actions include inhibition of serotonin re-uptake,
voltage gated K
+
channels and dopamine re-
uptake.
Ketamine acts as a postsynaptic antagonist at specific
excitatory synapses in the CNS. Glutamate is the
principal excitatory amino acid (EAA) in the brain.
Glutamate neurotransmission participates in various
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Other Medications and Adjuvants in Pain Management
forms of neuronal plasticity, including an activity
dependent change of synaptic efficacy, thought to
underlie learning memory and development [13,
51]. Excessive glutamate transmission contributes
to pathological processes such as epilepsy and
neuronal degeneration following ischaemia and
hypoglycaemia, and is thought to contribute to
chronic pain states.
e NMDA glutamate receptor consists of five
subunits surrounding a central ion channel. Non-
competitive blockade at the phencyclidine site is
produced by dissociative anaesthetics, with their
affinities in the descending order, dizocilpine (MK
801) > phencyclidine > ketamine. e analgesic
action in subanaesthetic doses was first studied by
Domino in 1965 [21, 63]. e sites of analgesic
action are likely to be located at both spinal and
supraspinal levels. In animal models, ketamine
blocks higher centres such as the nucleus reticularis
gigantocellularis and suppresses activity of laminae
I and V in the spinal cord [5, 46].
e dorsal horn is the site of termination of
the primary afferents. e NMDA antagonist
properties of ketamine may attenuate the “wind up”
and central sensitisation phenomenon, and reduce
areas of postoperative secondary hyperalgesia [17,
22, 70].
Morphine tolerance is due to a central hyperactive
state resulting from neuronal plastic change
within the spinal cord and plays a critical role in
hyperalgesia associated with nerve damage and
inflammation. Such changes involve EAA mediated
intracellular cascades, including translocation of
phosphokinase C and nitric oxide production.
Similar EAA receptor mediated mechanisms are
involved with morphine tolerance in the superficial
laminae of the spinal cord. Ketamine has been
found to attenuate and reverse morphine tolerance
in rats. Dextromethorphan and ketamine have
been shown to reduce abstinence symptoms in
opioid addicts.
e S(+) and R(-) stereoisomers of ketamine show
differences in action. e S(+) isomer is more potent
and cleared faster than R(-) and smaller doses can
be used. Faster recovery of cognitive performance
occurs with S(+). Haemodynamic and endocrine
changes do not differ significantly.
Pharmaceutical preparations
Ketamine hydrochloride (Ketalar) is formulated for
clinical use as an injection containing 10 mg/ml,
50 mg/ml and 100 mg/ml.
Side eects
Critically ill patients with catecholamine depletion
may respond to ketamine with an unexpected
reduction in blood pressure and cardiac output.
Emergence reactions (dreams, hallucinations,
confusion) are more common with adults,
high doses and rapid administration, and are
reduced by premedication with benzodiazepines.
Cardiovascular effects (hypertension, arrhythmias,
sympathetic effect) are less common with the
subanaesthetic doses used in chronic pain.
ere is report of renewed interest in ketamine with
abuse at “rave” parties. e source of the drug is often
hospital and veterinary supplies. e drug obviously
needs to be kept secure in the hospital setting
Indications in chronic pain
conditions
Patients with pain conditions which have
nociceptive and/or neuropathic mechanisms may
benefit from ketamine. ere has been a significant
number of case reports of the analgesic action of
long-term ketamine used in postherpetic neuralgia
(IV, IM, SC and oral), post-amputation pain, post-
surgical neuropathic pain and other neuropathic
conditions.
Evidence-based literature
Hocking reviewed the literature on ketamine
from 1966 through August 2002 and suggested a
comprehensive treatment approach with the drug
[38]. He proposed performing a fully monitored,
placebo controlled intravenous infusion trial
of ketamine to assess therapeutic benefit. An
intravenous dose of 0.25–0.5 mg/kg is given slowly
over 30 minutes with pain assessments before and
after administration. If the patient is considered
a positive responder, then oral ketamine should
be commenced at 0.5 mg/kg taken immediately
before going to bed to minimise the likelihood of
side effects (level IV). He suggested increasing the
dose by 0.5 mg/kg as tolerated until pain relief is
obtained or intolerable side effects occur (level IV).
e mean effective dose from the literature is 200
mg/day (level II).
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398 Anne Miu Han CHAN
Overall, the magnitude of reported benefit from
ketamine in chronic pain is often little more than
what might be expected by a placebo effect. Unless
there is great interest in performing good quality
studies in this area, ketamine will remain a third-
line drug that is administered on the basis of weak
evidence in patients who have failed to respond to
routine pharmacotherapy [38].
Systemic Local Anaesthetic
Type Drugs
Both lignocaine and mexiletine are local
anaesthetic class 1B antiarrhythmic agents. e
local anaesthetic type drug stabilises the neuronal
membrane by inhibiting the sodium flux required
for the initiation and conduction of impulses.
Pharmacology
Mechanisms of action
It seems that the analgesic mechanism of systemic
lignocaine in peripheral nervous system injury is
through suppression of ectopic impulse generators
in the damaged peripheral nerve [28]. is is
achieved by the blocking of sodium channels.
Side eects
Adverse effects are usually minor, such as
light-headedness, somnolence, nausea and
perioral numbness. Serious central nervous and
cardiovascular side effects are uncommon with the
usual therapeutic doses. However, the therapeutic
index is narrow for this group of drugs.
Indications
Systemic local anaesthetic drugs have been used
in peripheral nerve injury, trigeminal neuralgia,
diabetic neuropathy and postherpetic neuralgia.
Other reported uses include fibromyalgia, migraine
and cancer related pain, although the effectiveness
for the latter indications was inconsistent
Evidence-based material
e best documented effective dose of intravenous
lignocaine was 5 mg/kg, which was well tolerated
when infused over 30 minutes. Mexiletine (225–
750 mg) caused minor adverse effects that were
dose related. Tocainide should not be used because
of its toxicity.
Local anaesthetic type drugs are effective in pain
due to peripheral nerve injury, but there is little
or no evidence to support their use in migraine or
cancer related pain [50].
Corticosteroids
Corticosteroids may have a role in the treatment of
bone pain due to metastatic bone disease [72], in
cerebral oedema due to either primary or metastatic
tumour [77] and in epidural cord compression
[33].
Dexamethasone tends to be the most frequently
used corticosteroid because of its high potency, long
duration of action and minimal mineralocorticoid
effects [14].
Pharmacology
Mechanisms of action
Corticosteroids may produce analgesia by a variety
of mechanisms, including anti- inflammatory effects
and reduction of tumour oedema, and potentially
by a reduction of spontaneous discharge in injured
nerves [76].
Side eects
Principal adverse reactions involve multiple
organs. Adverse effects are uncommon after a short
duration of treatment; risks increase with increased
dose and prolonged use. e side effects of steroids
are shown in Table 24.01.
Indications
Steroids have been used in the treatment of
refractory bone pain, cerebral oedema and epidural
cord compression. ey have also been used in
the treatment of aching, burning, lancinating
neuropathic pain, severe migraine headache, and
pain cause by malignant lesions of the brachial and
lumbosacral plexus. ere has been some use in the
treatment of myofascial pain with trigger points
[53]. e use of epidural steroids is covered in
Chapter 25 on interventional procedures for pain.
Cannabinoids
Cannabinoid receptors are present in the central
and peripheral nervous systems, although the
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399
Other Medications and Adjuvants in Pain Management
function of these receptors and the endogenous
ligands may yet be unclear [10]. It is well known
that cannabinoids have analgesic action and that
they are also effective antiemetic agents. In animal
studies, cannabinoids have been shown to reduce
the hyperalgesia and allodynia associated with
formalin, capsaicin, carrageenan, nerve injury and
visceral persistent pain. e use of cannabinoids
has been explored in pain syndromes which are
poorly managed.
Pharmacology
Side eects
e adverse psychological effects of cannabinoids
include psychomotor and cognitive impairment;
anxiety and panic attacks; and acute psychosis
and paranoia. Other adverse effects include dry
mouth, blurred vision, palpitations, tachycardia,
and postural hypotension. Cardiovascular effects
are generally mild and well tolerated.
Indications
Evidence-based material
A qualitative systematic review by Campbell et al.
concluded that cannabinoids are no more effective
than codeine in controlling pain [10]. ey also
have depressant effects on the CNS, which limit
their use. eir widespread introduction into
clinical practice for pain management is therefore
undesirable. Before cannabinoids can be considered
for treating spasticity and neuropathic pain, further
valid randomised controlled studies are needed.
Clonidine
Clonidine has proved to be a clinically useful
adjunct in clinical anaesthetic practice as well as in
chronic pain therapy because it has both anaesthetic
and analgesic-sparing activity.
Pharmacology
Mechanisms of action
Clonidine is a selective agonist at the alpha-2-
adrenoceptor receptors with a ratio of 200:1 (α2:
α1). It inhibits central sympathetic outflow through
activation of alpha-2-adrenergic receptors in the
medullary vasomotor centre. Clonidine is not a
pure alpha-2-adrenoceptor agonist. It also acts on
the nonadrenergic imidazoline receptors [44].
e alpha-2-adrenoreceptor agonists have analgesic
properties when given parenterally, epidurally
or intrathecally. Descending noradrenergic
antinociceptive systems originating in the brainstem
contribute to pain control by suppressing the spinal
centripetal transmission of nociceptive impulses.
ese pathways are activated by stimulation of
the locus coeruleus and dorsal raphe nucleus, and
analgesia may be mediated by noradrenaline release.
An alpha-2 A receptor subtype has been identified
in the substantia gelatinosa of the dorsal horn of the
spinal cord. Stimulation of these alpha-2 receptors
by intrathecal noradrenaline or specific agonists
inhibits the firing of nociceptive neurons stimulated
by peripheral A-delta and C fibres. Also, intrathecal
noradrenaline inhibits the release of substance P by
primary afferents of the dorsal horn and suppresses
the activity of wide dynamic range neurons evoked
by noxious stimulation. ere is evidence which
has suggested that the antinociception produced
by alpha-2-adrenoreceptor agonists may be due
to acetycholine release in the spinal cord. It has
been suggested that the spinal cord is the major
site of analgesic action of alpha-2-adrenoreceptor
agonists, and the epidural and intrathecal routes
have been considered preferable to the intravenous
route [44].
Pharmaceutical preparations
Clonidine hydrochloride is available in the form of
tablets (Catapres) of 0.1 mg, 0.2 mg and 0.3 mg; as
a transdermal therapeutic system (Catapres-TTS)
providing continuous systemic delivery of 0.1 mg,
0.2 mg and 0.3 mg over 24 hours; and an epidural
injection (Duraclon) containing 100 mcg/ml.
Side eects
e onset of cardiovascular side effects such as
hypotension and bradycardia is slow (30–60
minutes with oral medication) and needs careful
monitoring. e CNS side effect of sedation is
common. Sudden cessation of clonidine may result
in rebound hypertension, nervousness, agitation
and tremor.
Indications
Clonidine is used in neuropathic pain, for
supplemental relief of pain and muscle spasm in
fibromyalgia and in cancer pain. It is also used in
migraine prophylaxis
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