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280 Simon K.C. CHAN, Alice K.Y. MAN
Classication
Acute peripheral arterial events are classified as:
1. Aortic events — ruptured or acute
symptomatic aortic or iliac aneurysm, or
thoracic aortic dissection.
2. Acute thromboembolic events — limbs or
viscera.
3. Critical limb ischaemia: lower limb
intermittent claudication, rest pain, skin ulcer,
gangrene. About 90% of patients with severe
limb ischaemia end up with amputation.
Chronic critical limb ischaemia is defined
as ischaemic rest pain and ischaemic ulcers
or gangrene. is section will focus on the
management of intermittent claudication and
critical limb ischaemia in PAD, which are common
presentations to pain clinics.
Clinical Features
Intermittent claudication (derived from the Latin
word for “limp”) is the most common symptom
and is defined as leg pain that is sufficient to
cause the patient to stop, is produced by exercise
and relieved by rest, and is caused by arterial
occlusive disease [23]. e location of pain may
indicate the site of arterial occlusion: calf pain in
femoral, popliteal or tibial arterial occlusion and
hip, buttock, thigh pain suggestive of aorto-iliac
occlusion. e temporal relationship of pain with
exercise or rest may indicate the severity of the
disease. Walking distance, the pain-free distance
until being forced to stop, may serve as a good
indicator of the disease progress. Alternatively,
exercise testing with a treadmill can provide an
objective measurement of walking distance and
highlight other exercise limiting conditions such as
arthritis or breathlessness. e severity of PAD has
been classified according to its clinical symptoms
(Table 17.02).
Inspection of the skin, the colour and temperature
of the lower limbs and the nails, may reveal trophic
changes of chronic ischaemia: thin, dry skin, loss
of hair or subcutaneous fat and thickened nails.
Gangrenous changes, ulcer, previous amputation
and muscle atrophy may also be evident. Peripheral
pulses such as the dorsalis pedis and posterior
tibial artery may be absent. Motor deficits
indicate advanced limb-threatening ischaemia.
Sensory loss (usually secondary to DM) should be
documented.
Although a number of conditions can mimic
PAD (Table 17.03), a careful history and physical
examination can distinguish PAD from other
disorders. For example, pain arising from cauda
equina compression due to spinal stenosis is made
worse by walking, but the pain is also brought on
by prolonged standing and is not rapidly relieved
by rest.
Patients with PAD for consideration of invasive
intervention require imaging investigations to
define the anatomy of the lesion. Angiography is
used to delineate the anatomy and atherosclerotic
lesions before invasive therapy. However, invasive
angiography is not without risk, such as from
contrast reaction, and duplex ultrasound scanning
is an alternative to angiography; it is non-invasive
and can delineate specific lesions for suitable
endovascular treatment. Another alternative is
magnetic resonance angiography, which is also
non-invasive, but its cost is always an issue.
romboangiitis obliterans, on the other hand,
tends to occur between the ages of 40 and 45 years
and is found predominantly in men. Blood vessels
Table 17.03 Differential diagnosis of peripheral
arterial disease
Differential diagnosis of PAD
• Venous insufficiency
• Sciatica with nerve root compression
• Spinal stenosis with cauda equina compression
• Hip, thigh or buttock local pathology, such as
osteoarthritis
• Other arterial causes: traumatic, congenital, or
neoplastic
Table 17.02 Classification of PAD according to
severity
Fontaine classification of chronic leg ischaemia
Stage I Asymptomatic
Stage II Intermittent claudication
Stage III Ischaemic rest pain
Stage IV Ulceration or gangrene, or both
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Pain Associated with Medical Diseases 281
of both the upper and lower limbs can be affected,
and more than one limb is likely to be involved with
the pain typically beginning in the extremities.
Management
As 5-year mortality rate of 25–30% is associated
with symptomatic PAD. e goal of management,
in addition to the improvement of leg symptoms, is
to prevent systemic complications such as stroke and
myocardial infarction from ongoing atherosclerosis.
e reader is referred to the recent review on the
medical treatment of PAD for details of systemic
complication prevention in PAD [34]. Leg symptoms
can be improved with disease modification or
invasive interventions aimed at improving the blood
supply to the lower limbs; at the same time, pain
control is an important component in managing
patients with critical limb ischaemia.
1. Disease modification
(a) Smoking cessation — apart from reducing
systemic complications, smoking cessation
reduces claudication severity and the risk
of developing rest pain in patients with
intermittent claudication. In addition, total
smoking cessation is essential for patients
with TAO to prevent disease progression and
amputation.
(b) Exercise rehabilitation such as a structured
exercise programme can increase initial
claudication distance and maximal walking
distance [81].
(c) Optimise hyperlipidaemia control — using
weight reduction and a statin drug. Simvastatin
20–40mg/day has been shown to reduce the
incidence of claudication and improve pain-
free walking distance [63].
(d) Optimise hypertension control — use of a
beta blocker is no longer considered to be
contraindicated in PAD [68], and angiotensin
converting enzyme inhibitors may improve
walking distance [60].
(e) Cilostazol — a phosphodiesterase III inhibitor
with vasodilator and antiplatelet activity has
been demonstrated to improve maximum
walking distance and pain-free walking
distance. However, it remains contraindicated
in patients with PAD with coexistent cardiac
failure [34].
(f) Iloprost (a prostacyclin analogue) and
prostaglandin E1 have been found to reduce
pain and the amputation rate for PAD in a
recent meta-analysis [21].
(g) Anti-platelet agents — aspirin, although it
does not improve claudication, delays the
rate of progression and reduces the need
for intervention and graft failure in patients
after revascularisation intervention [34].
Clopidogrel is an alternative for patients who
do not tolerate aspirin.
(h) Anti-coagulants — heparin, low molecular
weight heparin or oral anticoagulant, provide
no benefit in intermittent claudication.
2. Invasive interventions
Endovascular stenting, percutaneous transluminal
balloon angioplasty and open surgical bypass or
endarterectomy should be considered for suitable
patients to improve the blood supply to the lower
limbs. e reader is referred to other literature for
details in this area.
3. Pain Control
Patients with critical limb ischaemia describe a
history of worsening claudication and progress to
nocturnal rest pain. Nocturnal rest pain, which
typically occurs once the patient is asleep, is due
to the reduction of systemic blood pressure thereby
further reducing perfusion of the foot. Patients
should be referred to a vascular surgeon for
consideration of urgent revascularisation. For those
who are on the waiting list for invasive interventions
or not candidates for revascularisation, for example
those with comorbidity or an unsuitable anatomy,
symptomatic pain relief with pharmacological
analgesia is required.
Research in analgesia for critical limb ischaemia has
been limited. Racemic ketamine was demonstrated
to give a dose-dependent analgesic effect in chronic
ischaemic pain from PAD, but with significant
“para-perceptual/dys-cognitive” side effects [65].
Transdermal buprenorphine together with spinal
ropivacaine-morphine infusion was shown to provide
better analgesia compared with spinal ropivacaine-
morphine alone for 30 days in patients with chronic
pain from PAD [10], but the technique may not
be feasible for patients outside the hospital setting.
e pain in critical limb ischaemia can be severe
and variable, seemingly spontaneous, even with
patients at rest in a constant ambient temperature,
and sometimes an opioid is required [65].
Hence, a stepwise analgesic approach similar to the
WHO analgesic ladder is advisable for managing
this group of patients. It is necessary to remember
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282 Simon K.C. CHAN, Alice K.Y. MAN
that neuropathic pain may be associated with PAD
and analgesia specific for neuropathic pain should
always be considered when managing these patients.
e choice of pharmacological agents, however, has
to be cautious, as these patients are usually elderly,
have vasculopathy, are on multiple medications and
have a high incidence of comorbidity. e treatment
strategy should, therefore, be individualised for
each patient.
If pain becomes intractable or intolerable side
effects develop from analgesics, interventional
pain therapies such as lumbar sympathectomy and
spinal cord stimulation should be considered.
4. Lumbar sympathectomy
Lumbar sympathectomy can be performed with
open, percutaneous or endoscopic access.
A previous study shows healing of gangrenous
ulcer (30%) and pain relief (70%) in patients
after phenol lumbar sympathectomy [54]. Careful
patient selection is important for improved outcome
and an ABPI >0.3 is associated with clinical
improvement (Table 17.04). Moreover, the patency
of the superficial femoral artery is demonstrated to
be related to the successful outcome of patients
[64]. ere is so far no established role for adjuvant
surgical sympathectomy to improve bypass graft
patency or efficacy. Common complications are
temporary neuralgia and unsatisfactory pain relief.
Please also refer to Chapter 27 for more details on
lumbar sympathectomy.
5. Spinal cord stimulation
e effects of spinal cord stimulation (SCS) in
PAD have been reviewed by Tiede et al. [86]
and it was found that SCS improves exercise
tolerance, amputation rate and pain. e
walking distance demonstrated an impressive
increment. e limb salvage rate in severe
PAD patients after SCS implantation was
found to be 96%. Patients with intermediate
preoperative microcirculatory status
demonstrated an improved amputation rate
(24% vs 48%, p=0.08) with SCS in a Dutch
multicentre randomized controlled trial [87].
Analgesic consumption was also significantly
reduced with SCS at 1, 3 and 6 months.
However, patients with gangrene and trophic
lesions >3cm2 may not benefit from SCS.
e beneficial effects of SCS on PAD appears to be
an alteration in blood flow to the ischaemic limb,
especially the microcirculatory flow. e proposed
mechanisms are:
(a) inhibition of the sympathetic activity
involving nicotinic transmission in the ganglia
and postganglionic alpha-adrenoceptors
(b) the role played by afferent fibres in the dorsal
root.
Significant complications of SCS in PAD patients
include failure (3–4%), infection (3–5%), lead
dislocation and breaks (11–36%), cerebrospinal
fluid leak (1%) and meningitis (0.5%) [44].
Although the role of SCS in refractory ischaemic
pain and functional improvement is promising, the
cost and inherent risks remain the major limiting
issues for its wide clinical application. More details
of SCS can be found in Chapter 29.
Coronary artery disease
Background
Angina is described as substernal chest pain
associated with squeezing, tightness, aching,
dullness, fullness, heaviness or pressure, typically
aggravated by exertion or emotional stress.
Refractory angina pectoris is the term applied
when patients who, despite optimal medical
therapy, have both angina and objective evidence
of ischaemia and are not considered candidates for
revascularisation [99]. is section will focus on
alternative therapies for refractory angina and give
a brief discussion on non-cardiac chest pain, both
Table 17.04 Indications for lumbar sympathectomy
[22]
Indications for lumbar sympathectomy
• Patients with inoperable distal arterial
occlusive disease secondary to atherosclerosis
or TOA
• Revascularisation procedure is contraindicated
in case of inadequate run-off
• ABPI >0.3
• Superficial necrosis limited to digits
• Absence of neuropathy
• Symptom relief after diagnostic lumbar
sympathectomy
• Acceptable surgical risk for a retroperitoneal
approach
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Pain Associated with Medical Diseases 283
of which are common entities presented at the pain
clinic.
Pathophysiology
Reduced blood supply to the myocardium because
of coronary atherosclerosis, spasm, or a combination
of both leads to myocardial ischaemia and usually
manifests as angina pectoris. Anginal pain is
primarily nociceptive and arises from the adventitia
of the coronary arteries and the myocardium. is
afferent impulse travels along the sympathetic
nerves to the upper four thoracic sympathetic
ganglia and continues to enter the T1–T6 spinal
cord segments [22].
Angina serves as a warning sign to patients as
the reduction in their activity will limit the
severity of the ischaemic injury; and this potential
preconditioning effect is “beneficial” in nature [12].
In contrast, uncontrolled ischaemic pain would
have potentially devastating effects on the already
compromised heart, as indicated below:
1. Activation of the sympathetic nervous system
resulting in hypertension, tachycardia,
increase in myocardial contraction and
vascular resistance.
2. Increase in myocardial oxygen demand.
3. A coupled reduction in myocardial oxygen
supply due to coronary vasoconstriction.
4. e imbalance of myocardial oxygen supply
and demand further exacerbates the myocardial
ischaemia, creating a viscous cycle.
Management
e management of angina has been reviewed
by Yang et al. [99] and includes: anti-ischaemic
therapy; anti-platelet/anticoagulant therapy; risk
factor modification; and revascularisation. Optimal
standard therapy includes administration of a beta-
blocker and calcium channel blocker to achieve the
lowest heart rate and after-load reduction. A long-
acting nitrate and angiotensin-converting enzyme
inhibitor are also recommended. Aggressive risk
factor modification, such as smoking cessation,
cholesterol-modifying agents and exercise training
are essential.
Symptomatic control
When medical treatment is optimised and surgical
treatment not an option, symptomatic relief
becomes the only possible treatment. Morphine
is commonly included in the management of
angina, but its role in refractory angina is not
established. In our experience, a weak opioid like
tramadol can be successful in symptomatic control.
Other pharmacological therapies which have been
shown to be effective in refractory angina include
[99]: ranolazine — a fatty acid oxidation inhibitor
that can reduce oxygen demand; ivabradine — a
specific If ion channel inhibitor to reduce heart rate
and myocardial oxygen demand without a negative
inotropic effect; nicordanil — a nicotinamide ester
to decrease preload and after-load by vasodilatation;
L-arginine — to improve blood flow by coronary
dilatation; and transdermal testosterone for men
and oestrogen for women — to cause coronary
dilatation.
If and when patients fail to respond to
pharmacological intervention and become
incapacitated by their symptoms, alternative
therapies can be considered. ese have been
classified as: non-invasive non-pharmacological
(transcutaneous nerve stimulation and enhanced
external counterpulsation); and invasive therapies
(spinal cord stimulation and transmyocardial
revascularisation) [29].
1. Transcutaneous electrical nerve stimulation
Transcutaneous electrical nerve stimulation
comprises a neurostimulator unit and two
electrodes. An electrode is placed in the dermatome
with the highest intensity of pain and the other in
the opposite dermatome. e provision of 15–50
mA pulses at a frequency of 70 Hz for 1 hour three
times a day with an additional 1 to 10 minutes of
therapy on an as needed basis has been studied
[52]. e treatment group showed better exercise
tolerance during the stress test and reduction of
angina symptoms. Side effects encountered include
skin irritation, breakdown at the electrode sites and
paraesthesia.
2. Enhanced external counterpulsation
Enhanced external counterpulsation (EECP) is
classified as a class IIb indication (usefulness/efficacy
is less well established) device [29]. Based on the
concept of counterpulsation, it comprises three
pairs of pneumatic cuffs placed around the lower
extremities at the level of the calves, lower thighs
and upper thighs [99]. e cuffs are sequentially
inflated when triggered by a corresponding
electrocardiographic signal of systole and diastole.
e beneficial effect of EECP may be due to non-
specific placebo effects and haemodynamic factors
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284 Simon K.C. CHAN, Alice K.Y. MAN
similar to the intra-aortic balloon pump, release
of vascular endothelial growth factor and training
effects of the skeletal muscle [76]. It has been shown
that EECP improved angina symptoms and quality
of life at 2 years follow-up [77].
3. Spinal cord stimulation
Spinal cord stimulation (SCS) is a class IIb
indication device for refractory angina [29]. e
device consists of an epidural lead, pulse generator
and connecting wires. e epidural leads are placed
at the level of C7 through T1. e proposed
mechanism of action includes:
(a) Stimulation of the dorsal column, thus
inhibiting spinothalamic tract pain
transmission
(b) decrease in sympathetic tone
(c) improvement in myocardial blood flow.
Clinical studies have demonstrated that SCS
increases the time to onset of ST-segment
depression, increases exercise capacity during
treadmill testing, and reduces the number of anginal
attacks and use of nitroglycerin. SCS was shown to
be as effective as coronary artery bypass graft for
improving anginal symptoms with less procedure-
related mortality [53]. A cost utility study of SCS
in refractory angina, showed an annual saving of
US$8,430 and the recovery of the cost of the SCS
system in 15 months, due mainly to a reduction in
invasive testing [15]. Despite the fact that results of
studies on SCS appear promising, the intermediate
and long-term benefit is yet to be determined.
4. Transmyocardial revascularisation
Transmyocardial revascularisation (TMR) improves
oxygen delivery to myocardial cells using either a
carbon dioxide or holmium:YAG laser to generates
25–40 artificial conduits in the subendocardium
via the left thoracotomy approach. e suggested
mechanisms include angiogenesis because of
growth-factor release, denervation of pain fibres
by laser and placebo effect. Although TMR is a
class IIa indication (weight of evidence favours
efficacy) device for refractory angina [29], a lack
of randomised controlled trials and its invasiveness
have caused its use in the clinical setting to decline.
Percutaneous myocardial revascularisation is
similar, but performed percutaneously.
It should be noted that of all the therapies discussed
above, EECP is the most widely used and is the
only FDA-approved treatment for refractory angina
[99]. None of the therapies, including EECP, have
been shown to improve mortality in refractory
angina, but they are able to improve symptoms and
quality of life.
Non-cardiac chest pain
Non-cardiac chest pain (NCCP) is defined as chest
pain not due to cardiac ischaemia or other major
physical disorders.
Epidemiology
A population-based study in Hong Kong has shown
that NCCP was present in 13.9% of subjects; gastro-
oesophageal reflux disease (GERD) was found in
51%, while 34% consulted a physician because of
chest pain [96]. Factors found to be associated with
the seeking of medical attention included female
gender, presence of GERD and the affect of NCCP
on social life.
Aetiology
A number of conditions can lead to chest pain
of non-cardiac origin (Table 17.05), but of these
GERD is the most common. Patients experience
heart burn, sometimes associated with an abnormal
pH test and an endoscopy finding of oesophageal
erosion [25].
Patients with “Syndrome X” have typical anginal
pain with ST-depression on electrocardiogram
during an exercise stress test, while subsequent
angiography does not show any coronary
obstruction. ere may be occlusions or spasm in
the microvasculature around the heart, resulting in
tissue ischaemia and pain [84].
Diagnosis and management
Patients presenting with chest pain should be assessed
by history, physical examination and relevant
investigations to exclude a cardiac or other serious
origin of the chest pain, such as aortic dissection.
Table 17.05 Causes of non-cardiac chest pain
• Gastro-oesophageal reflux disease
• Visceral hypersensitivity
• Psychological origin
• Oesophageal dysmotility, altered central
processing of oesophageal stimuli and
autonomic dysregulation, etc.
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Pain Associated with Medical Diseases 285
Once non-cardiac chest pain has been diagnosed,
patients should be referred to a gastroenterologist
[25]. However, symptoms such as dysphagia,
odynophagia, weight loss and anorexia should alert
physicians that upper endoscopy is needed to detect
any mucosal abnormalities. In the absence of these
alarming symptoms, an empirical trial of a double
dose-proton pump inhibitor (PPI) is warranted
for 2–3 months. Titration to a maintenance dose
should follow if there is subsequent improvement
in symptoms. Otherwise, oesphageal manometry
to detect achalasia and spastic motility disorder is
suggested in an effort to identify other oesophageal
causes of NCCP. Nitrate and calcium channel
blockers have been used in non-GERD non-cardiac
chest pain.
Abnormal pain perception, psychiatric disorders
and pain-coping strategies should be explored in
patients with NCCP. Apart from pharmacological
treatment with imipramine [16] or sertraline [90],
coping-strategy training has also been shown to
significantly reduce pain, improve psychological
symptoms like anxiety and depression, alleviate
psychological distress and improve the physical
disability [43, 89].
Pain and Infectious
Diseases
Human immunodeciency virus
disease
Background
e human immunodeficiency virus (HIV) is a
retrovirus which infects the cells of the immune
system in humans leading to a decline in the body’s
defences against disease. e clinical features of
HIV-infected patients correlate with the CD4+T-
cell count. Patients are generally asymptomatic
at CD4 count >500cells/mm3. However, when
the CD4 count is <200 cells/mm3, a range of
opportunistic infections and unusual malignancies
can manifest themselves, leading to the diagnosis of
full-blown acquired immunodeficiency syndrome
(AIDS). A recent survey has found pain to be the
commonest symptom in stage 4 AIDS patients
with 98% prevalence [59].
Until the early 1990s, HIV disease, once it had
progressed to full-blown AIDS, was a rapidly fatal
illness. However, with the development of highly
active anti-retroviral therapy (HAART) in the
mid 1990s, HIV-related mortality and morbidity
has been dramatically reduced, especially in the
industrialised world. e mortality fell from 29.4
deaths per 100 patient-years in 1995 to 1.3 in
2004, with an increase in non-AIDS diseases as the
cause of death, including hepatic, cardiovascular,
pulmonary diseases and non-AIDS malignancies
[62]. e current median survival is estimated to
be 3 years, with a >75% chance of living 1 year
after diagnosis of AIDS in Australia [30]. e
introduction of HAART has altered the course of
HIV disease and has prolonged the life of AIDS
sufferers. Nevertheless, severe illnesses are likely to
emerge in these patients eventually. In addition,
the prolonged life span also results in an increase in
prevalence of some pain syndromes, such as HIV-
associated neurocognitive impairment, in these
patients, which imposes a new challenge in pain
management [48].
Epidemiology
It was estimated that 38.6 million (33.4–46.0
million) people worldwide were HIV positive at
the end of 2005. In addition, 4.1 million become
newly infected with HIV and 2.8 million die due
to AIDS each year [88]. Although the prevalence
(the proportion of people living with HIV) has
been levelling off since the late 1990s, the number
of people living with HIV has continued to rise
[88], and there is disparity in the prevalence
between the developed and developing world. e
number of new HIV infections has declined since
the mid-1980s in developed countries as a result
of effective prevention strategies such as public
education, blood screening and needle-exchange
programmes. Estimating HIV/AIDS prevalence
has become difficult in the industrialised countries
since the introduction of HAART as the natural
course of HIV disease has been altered. At the
end of 2003, it was estimated that over 1 million
people in the in United States were suffering from
HIV or AIDS, with 40,000 new cases diagnosed
each year [20]. In Australia at the end of 2000,
there were more than 10,000 people infected
with HIV and 700 new cases diagnosed each year
[30].
e prevalence in developing countries, compared
with the Western world, remains alarming. It
was estimated that 1.5 million people were HIV-
positive in China in 2003 [91], but the figure fell
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286 Simon K.C. CHAN, Alice K.Y. MAN
to 650,000 in 2006, as reported by the Chinese
government, a figure lower than that of the 5 million
in neighbouring India [92]. In South Africa, on
the other hand, AIDS is the leading cause of death
with 4.7 million people HIV-positive and 20.1%
of adults (aged 15–49 years) living with HIV/AIDS
[30].
e first patient was diagnosed with AIDS in Hong
Kong in 1984. It remains a relatively uncommon
condition in Hong Kong with 1,215 heterosexually
or homosexually infected patients reported from
1987 to 2000 [95]. Although the prevalence of
HIV is low, it may signal a pre-epidemic given
the presence of ongoing risk behaviours such as
unprotected sex [95].
Pain prole
In common with cancer patients, patients with HIV/
AIDS frequently experience pain. e pain tends to
be of more than one type, involves more than one
location and increases in intensity as the disease
progresses [40]. e prevalence of significant pain
ranged from 30% in the early stage of the disease
to 60–70% in institutionalised AIDS patients in
a 1996 International Association for the Study
of Pain (IASP) report [40]. e common sites of
pain with their incidence were: rheumatologically
related pain (72%), dysphagia and odynophagia
(30%), oral cavity pain (10–30%), chest pain
(22%), abdominal pain (10–30%), peripheral
neuropathy (15–20%) and headache (10–15%)
[61]. A recent survey of patients with stage 4 AIDS
in South Africa, however, revealed that pain was
the most common symptom with a prevalence of
98%; the top five sites of pain were lower limbs
(66%), mouth (50%), head (42%), throat (40%)
and chest (17%) [59]. Depression, which is usually
associated with chronic pain, was also found in this
group of patients; the incidence of lowered mood
and a feeling of hopelessness were 70% and 30%
respectively [59].
Pathophysiology
e mechanism of pain in HIV/AIDS is
multifactorial with diverse aetiologies. Nociceptive
pain can be secondary to combinations of
inflammation including autoimmune responses;
infection especially opportunistic infection; and
neoplasms such as lymphoma or Kaposi’s sarcoma.
Neuropathic pain in HIV/AIDS patients secondary
to neuropathy is common with a prevalence of up to
50% and can be due to direct HIV viral infection to
the central or peripheral nervous system; secondary
infection by other pathogens; immune-mediated
demyelination; and neurotoxicity secondary to
HAART, alcohol, nutritional deficiency and/or
other drugs such as anti-mycobacterials and anti-
neoplastics [50].
Clinical features
As almost all organ systems are potential targets
for HIV, various pain syndromes and their origins
have been described and reviewed by O’Neill et al.
[61].
1. Gastrointestinal pain syndromes
Pain in HIV disease can arise anywhere along the
gastrointestinal tract including the oral cavity,
oesophagus, anus and rectum, as well as the
hepatobiliary tract and pancreas. Candida infection
is the most common cause of pain in the oral
cavity and oesophagus, followed by ulcers from a
variety of organisms, including viruses, fungi and
bacteria implicated in necrotising and ulcerating
infections. Infection is also an important source
of pain in the anorectal region such as is caused
by perirectal abscesses, cytomegalovirus proctitis,
fissure-in-ano and herpes simplex infection. Right
upper quadrant pain from a hepatic or pancreatic
origin can have an infectious cause or be drug-
induced. Cytomegalovirus, cryptosporidiosis and
mycobacteria are the most common infectious
agents in cholecystitis, sclerosing cholangitis,
hepatitis and pancreatitis. Drug-induced hepatitis
and pancreatitis is commonly found secondary to
antiviral agents with an incidence of between 7–
10%.
2. Chest pain syndromes
Infectious causes of chest pain include Pneumocystis
pneumonia, oesophagitis, pleuritis, pericarditis
and postherpetic neuralgia. Kaposi’s sarcoma and
lymphoma are the common neoplastic causes
of chest pain. Protease inhibitors (PIs), a main
component of HAART, have been shown to have
deleterious metabolic effects such as dyslipidaemia
and insulin resistance in patients taking them.
Patients on PIs were noted to have a higher risk of
developing coronary artery disease with a relative
risk range from 1.26 to 2.56; the risk increases as
the duration of treatment lengthens [37]. Although
it remains controversial as to whether the rate of
coronary events is increased in HIV patients,
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Pain Associated with Medical Diseases 287
myocardial ischaemia should be one of the
differential diagnoses in HIV patients with chest
pain, especially in young males on PIs [37].
3. Headache
e differential diagnosis of headache in patients
with HIV includes HIV encephalitis and atypical
aseptic meningitis, opportunistic infections (such
as toxoplasmosis and cryptococcus), AIDS-related
central nervous system neoplasm, sinusitis, tension,
migraine and azidothymidine (AZT)-induced
headache. More ominous causes of headache
should be sought for a patient with a T-cell count
of below 200 [40].
4. Neuropathic pain syndromes
A variety of neuropathies have been described in
HIV/AIDS patients with mechanisms as highlighted
above. However, the most frequently encountered
neuropathy is symmetrical predominantly sensory
painful peripheral neuropathy, known as distal
sensory polyneuropathy (DSP) which occurs in
about one-third of all HIV-infected patients. e
most likely mechanisms of DSP are immunological
dysfunction secondary to HIV, and the neurotoxic
effects of antiretroviral drugs (particularly
dideoxynuclosides); intra-epidermal nerve fibre
density from skin biopsy was found to be a valuable
marker of severity [50].
5. Rheumatological pain syndromes
Several types of painful arthritis and arthropathies
have been reported with HIV/AIDS. ese include
non-specific arthralgia, reactive arthritis, psoriatic
arthritis, HIV-associated arthritis, aseptic arthritis,
with Reiter’s syndrome being the most frequently
reported. Muscle pain, which is common in HIV
patients, is due to myopathy and polymyositis,
which may be secondary to HIV infection or
antiretroviral therapy, in particular AZT.
Management
Due to the progressive nature and inevitably fatal
course of HIV disease, as well as the multiplicity
of pain occurring concurrently and the profound
effect of severe pain on quality of life during the
advance stage, HIV pain is considered to be similar
to cancer pain. Hence, the approach used in the
management of cancer pain can also be applied to the
management of AIDS-related pain. When disease-
specific therapy is not available, a pharmacological
approach following the WHO analgesic ladder
using opioids and co-analgesics is the mainstay of
treatment for end-stage AIDS patients.
However, the altered course of HIV disease resulting
from the development of HAART, and the higher
prevalence of psychiatric comorbidity, such as
psychosocial problems and chemical dependence,
in HIV patients, means that HIV/AIDS is seen as
more of a chronic disease state than a progressive
terminal illness, as previously thought. erefore,
a multimodal approach using the “pyramid-plus-
ribbon” contemporary cancer pain management
is advocated as being more appropriate in AIDS-
related pain [30]. is approach emphasises
the importance of disease-specific therapy,
psychosocial interventions and physical modalities,
in addition to the analgesic ladder (Fig. 17.1). It
is particularly important in managing the AIDS
pain patient, because therapies such as prophylaxis
for preventing opportunistic infections may be the
most appropriate palliative treatment in terminal
AIDS patients.
e treatment of HIV-associated neuropathy
has been reviewed by Luciano et al. [50] and to
date the only proven effective treatment for DSP
is mainly symptomatic. Lamotrigine was shown
to be effective in reducing pain in DSP but not
in dideoxynucleoside-induced polyneuropathy,
whereas gabapentine is effective in both.
Furthermore, human recombinant nerve growth
factor appears to offer promising improvement
in neuropathic pain and pain sensitivity.
Although it is known that antiretroviral agents,
dideoxynucleoside in particular, can cause
neuropathy, the enhanced viral suppression
from HAART may actually improve or decrease
the frequency of certain types of neuropathies
in HIV/AIDS. erefore, HAART should be
considered for patients with neuropathy especially
with evidence of viral replication.
It is not uncommon to encounter HIV patients
with a past history of substance abuse; hence,
when managing these patients, it is important to
distinguish between active users, individuals in
methadone maintenance and those in recovery, so
that pain management plans can be individualised.
It is also recommended that clear goals and
conditions for opioid therapy are defined: set limits,
make consequences clear, use written contracts and
establish a single prescriber.
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288 Simon K.C. CHAN, Alice K.Y. MAN
Severe Acute Respiratory
Syndrome
Background
Severe acute respiratory syndrome (SARS) is a
recently emerged infectious disease caused by the
SARS coronavirus which led to a global outbreak
in 2003. As at 31 July 2003, there were 8,098
probable cases reported and a death toll of 774
with an overall mortality rate of 9.6% [38]. e
majority of patients improved with treatment, but
20–36% required intensive care admission and
13–26% progressed to acute respiratory distress
syndrome (ARDS) requiring ventilatory support.
In addition to supportive therapies, SARS patients
were treated with antiviral agents — ribavirin,
lopinavir or ritonavir — and, if they deteriorated
further, were given high-dose methylprednisolone
0.5 g daily to avoid immunopathological lung
injury [38]. Post-SARS patients were followed
up for 1 year and were found to have favourable
pulmonary recovery comparable to post-ARDS
patients. However, when compared with normal
subjects, post-SARS patients were found to have
a significantly lower 6-minute walk distance
and impairment of health-related quality of life
as measured by SF-36, which may have resulted
from generalised muscle weakness and myopathy
[39].
Pathophysiology
e effect of pain on post-SARS patients is still
unclear as the literature on this issue remains scant.
However, it appears that pain is common in SARS
patients, at least in the acute phase. Although fever
and respiratory symptoms were the predominant
clinical features, 45–61% of SARS patients had
myalgia [38] and 32% had raised creatine kinase
[47] on presentation. In addition, 53% of patients
who had no prior joint symptoms nor predisposition
to osteonecrosis developed large joint pain after
SARS infection, but only 5% showed evidence of
subchondral osteonecrosis on magnetic resonance
imaging after recovery from SARS [33]. In a
small series of 30 post-SARS patients (published
in Chinese), 87% developed arthralgia [27] and
there is a case report of fibromyalgia [85]. A
number of mechanisms have been implicated for
these musculoskeletal involvements, including
critical illness polyneuropathy and/or myopathy;
steroid-induced myopathy and osteonecrosis;
deconditioning due to prolonged confinement;
and SARS-induced myopathy and arthralgia [33,
39].
Management
e pain management for post-SARS patients poses
a number of challenges: unknown mechanism of
pain in SARS, uncertain natural course of SARS
recovery, potential litigation and high prevalence
of mood and psychological disturbances [19].
Treatment is mainly supportive and pain should
be managed with a multidisciplinary approach
using multimodal analgesia, physical therapy
and psychotherapy. It is important to exclude
osteonecrosis and to consult an orthopaedic
surgeon if indicated clinically, especially in patients
who have received more than the equivalent of 3 g
prednisolone for SARS treatment [33].
Pain and Haematological
Disorders
Haemophilia
Background and pathophysiology
Haemophilia is a sex-linked genetic coagulation
disorder due to qualitative or quantitative defects
of clotting factors. Although all clotting factors
can be affected, defect in Factor VIII (haemophilia
A) and Factor IX (haemophilia B) are the most
common inherited coagulation disorders. e
severity of haemophilia depends on the plasma
concentration of clotting factor and is graded
as severe if the concentration is less than 1%.
e major complication of haemophilia is intra-
articular bleeding to the large joints leading
to repeated haemarthrosis, chronic synovitis,
epiphyseal overgrowth, destruction of cartilage and
eventually joint deformity in the adolescent. e
pain and joint deformity have a profound effect
on the function and quality of life for haemophilia
sufferers [35].
Management
e disease process can be modified with
prophylactic factor replacement to maintain
plasma factor level >1% between 1 and 3 years of
age to prevent joint destruction [9]. Recombinant
factor is now preferred to avoid disease transmission
of HIV or hepatitis viruses. Corticosteroids
have been used to decrease synovium in chronic
synovitis with good but temporary results. Non-
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Pain Associated with Medical Diseases 289
steroidal anti-inflammatory drugs have a limited
role in this situation due to the associated risk of
bleeding. However, celecoxib, a cyclo-oxygenase-2
inhibitor, has been shown to be safe and effective
in treating chronic synovitis and joint pain in
haemophilia [70]. In situations where medical
prophylaxis is not possible, such as unavailability
of factor product or development of inhibitors
to transfused product, open or arthroscopic
surgical synovectomy can effectively retard the
pathological process of haemophilic arthropathy.
More recently, intra-articular injection of
chemical or radioisotope sclerosing agent has been
used as the alternative for surgical synovectomy
and found to have short-term effect [35]. Total
joint replacement may be the ultimate procedure
for haemophilic arthropathy and can bring
considerable improvement in joint movement and
pain relief. It is important to stress that supportive
physical therapy is a lifelong need and should
always be part of an integral management plan for
this group of patients.
Sickle cell disease
Background
Sickle cell disease is an inherited haemoglobin
disorder. Chronic haemolytic anaemia occurs
in homozygous inheritance of haemoglobin S
characterised by the sickle-shaped red blood cells
causing vaso-occlusion and infarction. roughout
their lives the homozygotes are affected by recurrent
painful episodes which are highly variable in
frequency and severity among patients. Advances
have been made recently in the understanding and
treatment that significantly improve outcomes in
sickle cell disease. Guidelines and recommendations
are readily available to assist physicians in managing
these patients [55, 71].
Management
Interventions recommended to modify the disease
processes from childhood to avoid permanent
damages include [55]: prophylactic antibiotics
with daily penicillin V potassium from 2 months
of age until age 5 years; childhood immunisation
with 7-valent pneumococcal conjugate vaccine
and 23-valent polysaccharide pneumococcal
vaccine for children less than 2 years and older
than 2 years respectively; hydroxyurea, which can
increase haemoglobin F levels and improve red cells
deformability, should be considered for those who
have frequent severe painful episodes.
Most sickle cell disease patients with acute painful
episodes have been under-treated. eir minority
ethnic origin and lower socioeconomic class;
recurrent multiple presentations to hospital with
pain; and fear of opioid dependence all imposed
a barrier to the proper management of these
patients. is situation prompted the publication
of guidelines to assist the management of pain
associated with this disease [71]:
1. Arrangement for fast-track hospital admission
and assessment.
2. Aggressive and early pain control according to
the WHO analgesic ladder.
3. Morphine is the first choice of opioid
analgesic and patient-controlled analgesia is
recommended if facilities are available.
4. Non-pharmacological pain management such
as psychological and physical approaches are
beneficial.
5. Other general measures, such as rehydration,
oxygen supplement, antibiotics and blood
transfusion if indicated.
Pain and Pancreatic
Disorders
Acute pancreatitis
Background
Acute pancreatitis is an acute inflammatory
disorder of the pancreas caused by an intracellular
activation of pancreatic digestive enzymes. It
represents a spectrum of disease ranging from a
mild, self-limiting course to a rapidly progressive,
potentially fatal illness. e destruction of
pancreatic parenchyma induces a systemic
activation of coagulation, kinin, complement and
fibrinolytic cascades with liberation of cytokines
and reactive oxygen metabolites which, in severe
cases, can lead to shock, acute renal failure and the
acute respiratory distress syndrome. Nevertheless,
in 70–80% of patients with acute pancreatitis, the
disease is mild and responds to supportive measures
alone.
Management
e principle of management of acute pancreatitis
includes: monitoring of vital signs, fluid
replacement, correction of electrolytes disturbance,
nutritional support, prevention of local and
systemic complications, and pain relief.
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