Guide to Pain Management in Low-Resource Settings

How can neuropathic pain               
be diagnosed?
A thorough medical history and examination are essen-
tial. Th
  e patient’s description of the pain quality often 
provides a fi rst indication of the presence of neuropath-
ic pain. Common verbal sensory pain descriptors are 
throbbing, pricking, aching, tender, numb, and nagging. 
However, descriptors such as burning, lancinating, or 
hot might be used as well. Other characteristics are pain 
projection and pain radiation along a course of nerves 
with either segmental or peripheral distribution, when 
the pain has a glove-like distribution, or is attributed to 
a dermatome. Increasing pain when lying down, local-
ized in the midline of the back with or without radia-
tion, and midscapular or bilateral shoulder pain might 
be associated with neuropathic pain as well. Paresis or 
muscular weakness and pain of an upper extremity are 
strong evidence of a plexopathy.
Screening tools such as painDETECT, an easy-
to-use self-report questionnaire with nine items that 
do not require a clinical examination, might be used 
as well. Patients have to answer seven questions re-
lated to the presence of burning sensations, tingling or 
prickling sensations, light touch being painful, the pres-
ence of sudden pain attacks or electric shocks, cold or 
heat pain, numbness, and slight pressure being pain-
ful. Th
 e scope of answers ranges from never, hardly 
noticed, slightly, moderately, strongly, to very strongly 
and will be attributed a score of 0–5 each. Additionally 
persistent pain with pain attacks will reduce the total 
score (minus 1 point), pain attacks without pain in be-
tween will add 1 point, pain attacks with pain between 
them will add 1 point, and fi nally the presence of radia-
tion pain adds 2 more points. A fi nal sum score of 19 
or above strongly suggests the presence of neuropathic 
pain. PainDETECT has a specifi city and sensitivity of 
more than 80%. Alternatively the Leeds Assessment of 
Neuropathic Symptoms and Signs (LANSS) tool might 
be used. Th
  is screening tool contains 5 symptom items 
and 2 clinical examination items (clinical examination 
for allodynia and pinprick threshold is necessary). Th
 e 
sensitivity and specifi city is over 80% as well. Th
 is tool 
might also be used to show treatment eff ects.
Th
 ese fi rst signs of the presence of neuropathic 
pain should be followed by a careful neurological ex-
amination. Physicians should attend to somatosensory 
abnormalities, such as dysesthesias, hyperalgesia, hyp-
esthesia, and allodynia. Most of these features can be 
diagnosed with simple bedside tests. Dysesthesia is an 
abnormal painful sensation (e.g., burning, lancinat-
ing pain). Using a stub-point needle, hyperalgesia—in-
creased perception of painful stimuli—can be diag-
nosed. Hypoesthesia describes a reduced feeling or an 
increased pain threshold (anesthesia stands for the non-
perception of a stimulus). Allodynia is defi ned as pain 
induced by a normally nonpainful stimulus.

158
Rainer Sabatowski and Hans J. Gerbershagen
Th
 ermal allodynia (pain caused by moder-
ate heat or cold; a warm or cold fork or knife might be 
used) and dynamic allodynia (e.g., pain induced through 
contact with clothing; for the examination a cotton-
wool tip might be used) are distinguished. A tuning fork 
can be used to look for abnormalities in the perception 
of vibration. Elaborate tests such as neurography or 
quantitative sensory testing (QST) might be used, but 
often they are not available or in the case of QST, the 
impact on diagnosis and/or treatment is not yet clear. 
Radiographic examination such as magnetic resonance 
tomography might be added in cases when further inva-
sive treatments are considered.
How can pain due to plexopathy    
in lung cancer be treated?
Th
 e initial treatment approach for painful plexopathy 
should follow the guidelines of the World Health Orga-
nization (WHO). However, adjuvants (e.g., anticonvul-
sants, antidepressants, and corticosteroids) are of par-
ticular importance. Th
  ese adjuvants are recommended 
at every step of the WHO ladder and sometimes might 
even be a fi rst-line medication before starting with non-
opioid analgesics or opioids.
What are barriers to eff ective     
pain management?
From the physician’s perspective, common barriers 
include:
•  Lack of familiarity with diagnosing neuropathic 
pain.
•  Reliance on nonopioid analgesics such as diclofe-
nac or acetaminophen (paracetamol) alone (these 
analgesics are not recommended in the algo-
rithms for treating neuropathic pain).
•  Avoidance of opioids due to misconceptions and 
myths about opioids (e.g., fear of addiction and 
beliefs that neuropathic pain is not responsive, 
that opioids should only be used for dying pa-
tients, and that respiratory depression is a com-
mon side eff ect of opioids). Th
  ere is evidence that 
opioids do relieve neuropathic pain, and they are 
included into the treatment algorithms for neuro-
pathic pain.
•  Unavailability of opioids.
•  Fear of legal consequences when prescribing “il-
licit drugs.”
•  No knowledge of the use and indication of non-
analgesic drugs (e.g., anticonvulsants) in the pres-
ence of neuropathic pain.
From the patient’s perspective, common barri-
ers include:
•  No satisfactory information about the pain and 
the drugs being used (e.g., an antidepressant was 
prescribed, or no information was given about 
the rationale for using opioids).
•  Fear or prior experience of side eff ects (e.g., ad-
diction, dry mouth, erectile dysfunction, and 
drowsiness).
•  No treatment of side eff ects was provided.
•  Drugs are often not available in rural sites, or the 
drugs being prescribed by a medical center are 
too expensive.
What strategies should be followed 
when treating a painful plexopathy?
Primarily cancer-reducing strategies such as chemo-
therapy or radiotherapy should be considered, to reduce 
or minimize the direct impact of the tumor on the plex-
us. However, if this approach is not possible, palliative 
pharmacological strategies should be started. Palliative 
treatment approaches include several pharmacological 
and nonpharmacological options.
Anticonvulsants
Th
  ese drugs were primarily used in treating trigeminal 
neuralgia, but current studies give evidence of effi
  cacy 
in various neuropathic pain conditions. Carbamaze-
pine acts via blockade of voltage-dependent sodium 
channels. Th
  e starting dose is 100 mg twice a day up to 
a maximum of 1200–1600 mg/day. Side eff ects such as 
sedation are common, especially when the initial dose 
is too high or titration is too rapid. Nowadays, the use 
in cancer pain is limited due to potential risks such as 
bone marrow suppression, leucopenia, hyponatremia, 
and interaction with liver metabolism and therefore 
multiple drug interactions. Gabapentin, if available, 
should be used as fi rst-line medication. Gabapentin is a 
chemical analogue of γ-aminobutyric acid (GABA) that 
does not act as a GABA-receptor agonist, but binds to 
the α
2
δ-subunit of the voltage-dependent calcium chan-
nel in the spinal cord. Th
  e binding to these receptors 
inhibits the release of excitatory neurotransmitters. Ga-
bapentin is administered three to four times a day. Th
 e 
starting dose is 3 × 100 mg, and the maximum dose 

Lung Cancer with Plexopathy
159
around 2400 mg/day. Due to the drug’s common side 
eff ects such as drowsiness and sedation, a slow titra-
tion is necessary.
Antidepressants
Among the antidepressants, the tricyclic antidepres-
sants (TCAs) such as amitriptyline are most fre-
quently applied in neuropathic pain. TCAs have been 
studied extensively in noncancer pain patients. Th
 ey 
enhance the endogenous inhibitory pathways by in-
hibiting the presynaptic reuptake of serotonin and 
norepinephrine in spinal pain pathways. TCAs also 
have agonistic eff ects on histamine and muscarinic 
receptors, which contributes to side eff ects such as 
sedation and dry mouth. Additionally, there may be 
binding to sodium channels as well as inhibition of 
voltage-dependent calcium channels. Due to its seda-
tive eff ects, amitriptyline should be administered dur-
ing the evening and should be slowly titrated. Par-
ticularly in older patients, the initial dose should not 
exceed 25 mg. Th
 e maximum dose for cancer pain 
is approximately 75–100 mg/day. Contraindications 
might arise from preexisting cardiac diseases such as 
arrhythmias or conduction defects. Secondary anti-
depressants such as nortriptyline or desipramine are 
as eff ective as TCAs but are often better tolerated 
due to less side eff ects. Selective serotonin reuptake 
inhibitors (SSRIs) such as fl uoxetine are better toler-
ated as well, but they are also less eff ective in relieving 
neuropathic pain. New antidepressants with a mixed 
mechanism of action such as venlafaxine, paroxetine, 
or duloxetine seem to be eff ective as well, but for can-
cer pain management the evidence is sparse, and they 
are not available in many countries.
Opioids
Common fallacies about opioids include a lack of effi
  ca-
cy in neuropathic pain conditions. Th
  is belief has been 
proven not to be true. Th
  ere is abundant evidence dem-
onstrating the effi
  cacy of these drugs. However, neuro-
pathic pain may be less responsive to opioids compared 
to nociceptive pain. Opioids should be titrated indi-
vidually and carefully to fi nd out the optimal balance 
between benefi t and side eff ects. By combining opioids 
with adjuvants such as gabapentin, the dose of each 
drug can be reduced and the eff ect on pain relief is usu-
ally greater than using only one of those drugs. Th
 ere-
fore, a combined therapy should be considered in neu-
ropathic pain.
Among opioids, morphine is the best studied 
drug. It is a mu-receptor agonist. Morphine is available 
in immediate-release formulations and (in some coun-
tries) in sustained-release formulations. As the duration 
of action of the immediate-release formulation is ap-
proximately 4 hours, frequent administration is neces-
sary. Titration should start with 5–10 mg every 4 hours. 
On occurrence of breakthrough pain, an additional 1/6 
to 1/10 of the total daily morphine dose should be ap-
plied as an initial step. Later, the adequate dose to treat 
episodes of breakthrough pain must be adjusted ac-
cording to the individual patient’s needs and responses. 
In the case of painful procedures, immediate-release 
morphine might be administered approximately half 
an hour before the procedure (such as wound manage-
ment) will be performed. Th
  e most common side eff ects 
include sedation, constipation, nausea, and vomiting. It 
is essential to take care of side eff ects (for constipation, 
prescribe laxatives and advise the patient about fl uid in-
take; for nausea, prescribe antiemetics and inform the 
patient that nausea is often self-limiting). In cases of he-
patic dysfunction (e.g., liver cirrhosis), the duration of 
action might be prolonged, so dosing intervals should 
be extended. In renal impairment, dose reduction is rec-
ommended while maintaining the application intervals.
Other opioids to be used include tramadol, 
which is a synthetic opioid not only stimulating mu-re-
ceptors but also inhibiting the presynaptic reuptake of 
serotonin and norepinephrine. Dosage is every 4 hours 
for immediate-release formulations and three times a 
day for sustained-release formulations. When switch-
ing from tramadol, which is sometimes classifi ed as a 
“weak opioid,” to morphine, the conversion ratio has to 
be considered (e.g., 100 mg oral tramadol is equivalent 
to approximately 10 mg of oral morphine). Th
 e maxi-
mum dose of tramadol should not exceed 400–600 mg/
day. Among the side eff ects, there is a high prevalence 
of nausea and vomiting. In renal failure, intervals be-
tween doses should be increased. Th
 e recommended 
dose in the case of liver cirrhosis amounts to 50 mg ev-
ery 12 hours.
Oxycodone is a semisynthetic opioid that ac-
tivates the mu-receptor as well as the kappa receptor. 
Duration of action is 4 hours. Due to the better oral 
bioavailability the conversion ratio to morphine is 1:2 
(e.g., 5 mg oral oxycodone equals 10 mg oral morphine). 
Oxycodone should be used very carefully in situations 
of renal or hepatic dysfunction, due to the increased 
elimination half-life.

160
Rainer Sabatowski and Hans J. Gerbershagen
Transdermal fentanyl, a synthetic mu-receptor 
agonist, delivers fentanyl via a self-adhesive patch with 
a rate-limiting membrane. Due to the slow delivery, the 
patches have to be changed every 72 hours (in 20% of 
patients a new patch has to be applied every 48 hours 
due to end-of-dose failure). Th
 e conversion ratio to 
morphine is 100:1 (e.g., 120 mg morphine/day equals 
50 μg fentanyl/hour). Advantages over morphine are 
the absence of active metabolites. However, in the pres-
ence of renal dysfunction, sensitivity to the drug’s eff ect 
is increased. Liver cirrhosis does not seem to aff ect the 
pharmacology of fentanyl, but impaired liver blood fl ow 
or liver failure does so. Constipation is less pronounced 
as compared to morphine. Disadvantages include adhe-
sive problems and the slow onset of action (when the 
patch is applied for the fi rst time, a 12-hour gap before 
the onset of action has to be taken into account).
Methadone might be considered an important 
alternative and, in cases of severe plexopathy, even as 
a fi rst-line opioid. Methadone is a synthetic opioid act-
ing as a μ-receptor agonist, an NMDA-receptor block-
er, and a presynaptic serotonin reuptake inhibitor. Due 
to its long elimination half-life of 24 hours (up to 130 
hours), titration is sometimes diffi
  cult,  but  methadone 
can also be regarded as a long-acting opioid, which ne-
cessitates only three to four daily dosages. Th
 e usual 
dose begin with 5 mg q.i.d. for 2–3 days. For inadequate 
pain relief or breakthrough pain, an additional 5 mg 
might be administered. Switching to or starting with 
methadone might be diffi
  cult. For this reason an algo-
rithm is recommended. On day 1 treatment with pre-
existing opioids should be stopped. Oral methadone 
2.5–5 mg should be administered every 4 hours. For 
breakthrough pain 2.5–5 mg methadone might be used 
additionally (with a dosage interval of 1 hour). On days 
2–3, a dose maximal increment of 30% might be neces-
sary, if pain relief on day 1 was not suffi
  cient.  On  day 
4, 72 hours after initiating methadone therapy, the dos-
ing interval should be changed to t.i.d. (every 8 hours), 
and the intervals for breakthrough medication should 
be prolonged to 3 hours as well. If pain relief is still not 
adequate or if pain increases due to cancer progression, 
dose adjustments might be performed. Patients on very 
high oral morphine doses (>1000 mg/day) should start 
on day 1 with 50 mg methadone q.i.d. Over the follow-
ing days, dose adjustments should be performed as de-
scribed above. Due to its metabolism via cytochrome 
P-450, precautions have to be taken to prevent drug in-
teractions. Ketoconazole, HIV protease inhibitors, and 
grapefruit juice are responsible for magnifi ed  metha-
done eff ects, whereas corticosteroids, St. John’s wort, 
carbamazepine, and rifampin might lower the eff ect. 
Methadone might cause prolongation of the QT-inter-
val and may cause torsades de pointes ventricular tachy-
cardia. Th
  erefore in patients at risk of hypokalemia, car-
diac diseases, or cocaine abuse, methadone should be 
used carefully, and an electrocardiogram should be per-
formed, if available.
Corticosteroids
Corticosteroids, especially dexamethasone, are helpful 
when there is clinical evidence of nerve structure com-
pression or pain due to edema surrounding the metas-
tases. In cases of severe pain, doses of 16–24 mg a day 
should be prescribed initially. In cases of an emergency 
(spinal cord compression) initial intravenous doses of 
up to 100 mg, followed by 60 mg in three divided doses 
should be used. Steroids should be continued until oth-
er treatment approaches (radiotherapy, drug therapy) 
are initiated, after which dexamethasone can be tapered 
off  gradually. Dexamethasone has two other “side ef-
fects” that might be helpful for palliative treatment. It 
has an antiemetic eff ect and might increase the appetite. 
To increase appetite, dexamethasone can be prescribed 
continuously in a daily dose of 2 mg.
NMDA-receptor antagonists
Excitatory neurotransmitters, such as glutamate, play a 
major role in pain transmission at the spinal cord level. 
Glutamate activates the NMDA receptor, which is as-
sociated with phenomenon such as central sensitiza-
tion.  Ketamine, an NMDA-receptor antagonist and a 
drug used extensively in anesthesia, should be consid-
ered, especially in situations when opioid analgesia is 
not eff ective enough. Th
  e addition of oral ketamine ap-
proximately 10–25 mg t.i.d. should be combined with 
diazepam in low doses (e.g., 5 mg) to avoid psychotic 
symptoms associated with the use of ketamine.
Cannabinoids
Newer classes of drugs to treat neuropathic pain are 
cannabinoids. Th
  ere is evidence that oral delta-9-tetra-
hydrocannabinol (THC) and other cannabinoids might 
provide relief from neuropathic pain, improve appetite, 
and reduce nausea and vomiting. However, these drugs 
cannot be recommended in general, due to the lack of 
well-designed studies in the area of cancer-related neu-
ropathic pain.

Lung Cancer with Plexopathy
161
Nonpharmacological Approaches
Nonpharmacological treatment approaches include epi-
dural opioid application and continuous infusion of lo-
cal anesthetics via a brachial plexus catheter. However, 
catheter dislocation and infection might be regarded 
as a major obstacle in applying this form of therapy, es-
pecially in rural areas where anesthesiologists are not 
available. 
Cordotomy is a neurodestructive procedure in 
which the anterolateral spinothalamic tract is destroyed 
to produce contralateral analgesia. Th
  e pain has to be 
strictly unilateral and due to the frequent recurrence of 
pain, the life expectancy of the patient should be lim-
ited. Important neurological complications include pa-
resis, ataxia, phrenic nerve paralysis, and in long-term 
survivors a delayed onset of dysesthetic pain.
Pearls of wisdom
•  In the clinical evaluation certain pain descrip-
tors (e.g., burning or lancinating pain) reported 
by patients in combination with neurological 
signs (e.g., hypoesthesia, allodynia, or pathologi-
cal cold/warm thresholds) by bedside testing with 
simple tools (e.g., a cotton-wool tip, needle, or 
cold spoon) give strong evidence of a neuropathic 
pain syndrome.
•  In cases of neuropathic pain, a combination of 
anticonvulsants, antidepressants, and opioids 
is usually more eff ective compared to an opioid 
monotherapy.
•  Consider the use of methadone in cases of “in-
tractable” neuropathic pain syndromes.
References
[1]  Dworkin RH, O’Connor AB, Backonja M, Farrar JT, Finnerup NB, Jen-
sen TS, Kalso EA, Loeser JD, Miaskowski C, Nurmikko TJ, Portenoy 
RK, Rice AS, Stacey BR, Treede RD, Turk DC, Wallace MS. Pharmaco-
logic management of neuropathic pain: evidence-based recommenda-
tions. Pain 2007;132:237–51.
[2]  Jaeckle KA. Neurological manifestations of neoplastic and radiation-
induced plexopathies. Semin Neurol 2004;24:385–93.
[3]  Shen KR, Meyers BF, Larner JM, Jones DR. American College of Chest 
Physicians. Special treatment issues in lung cancer: ACCP evidence-
based clinical practice guidelines, 2nd edition. Chest 2007;32(Sup-
pl):290–305.
[4]  Vecht CJ. Cancer pain: a neurological perspective. Curr Opin Neurol 
2000;13:649–53.
Websites
National Cancer Institute: www.cancer.gov
World Health Organization: www.who.int
European Association for Palliative Care: www.eapcnet.org
Non-Small Cell Lung Cancer Treatment (PDQ®): 
www.meb.uni-bonn.de/cancer.gov/CDR0000062932.html

163
Guide to Pain Management in Low-Resource Settings, edited by Andreas Kopf and Nilesh B. Patel. IASP, Seattle, © 2010. All rights reserved. Th
  is material may be used for educational 
and training purposes with proper citation of the source. Not for sale or commercial use. No responsibility is assumed by IASP for any injury and/or damage to persons or property 
as a matter of product liability, negligence, or from any use of any methods, products, instruction, or ideas contained in the material herein. Because of the rapid advances in the 
medical sciences, the publisher recommends that there should be independent verifi cation of diagnoses and drug dosages. Th
  e mention of specifi c pharmaceutical products and any 
medical procedure does not imply endorsement or recommendation by the editors, authors, or IASP in favor of other medical products or procedures that are not covered in the text.
Guide to Pain Management in Low-Resource Settings
Th
 omas Jehser
Chapter 21
Lung Cancer with Breathing Problems
Why is important to know about 
pain in lung cancer?
Lung cancer is the most common lung tumor and the 
most common malignant disease. Th
 e incidence in 
Europe is estimated by the World Health Organiza-
tion (WHO) to be 38/100,000 inhabitants (in Africa 
9/100,000). It causes about 1.2 million deaths per year 
worldwide. Since 1953 it has been the most common 
cause of death by cancer within the male population, 
and since 1985 within the female population.