REVIEW
URRENT
C
OPINION
Management of neuropathic pain in children
with cancer
Stefan J. Friedrichsdorf a,b and Andrea Postier Nugent a
Purpose of review
Many children with cancer suffer from neuropathic pain. However, there are no published pediatric
randomized controlled trials (RCTs), nor agreed upon pediatric treatment recommendations. Pediatric
neuropathic pain in patients with malignancies is often underassessed and undertreated with ineffective
therapies.
Recent findings
This article describes main themes in the literature and commonly used treatment strategies.
Summary
A combination of integrative, rehabilitative, and supportive therapies with pharmacotherapy, including first
line medications such as NSAIDs, opioids, low-dose tricyclics, and gabapentinoids, appear to be successful
treatment strategies. There is a dearth of evidence regarding the management of neuropathic pain in
children with cancer; studies, especially RCTs, are desperately needed.
Keywords
cancer, neuropathic, pain, pediatric
INTRODUCTION
Despite increasing awareness about the causes and
treatment of pain in children with malignancies, the
majority of children with cancer still experience
pain [1]. A meta-analysis demonstrated the prevalence of neuropathic mechanisms in patients with
cancer pain older than 12 years between 19 and 39%
[2]. This article reviews management options of
neuropathic pain in children with cancer.
DEFINITION
The International Association for the Study of
Pain defines neuropathic pain as ‘. . .pain arising as
a direct consequence of a lesion or disease affecting
the somatosensory system [3].’ However, the definition also states ‘. . .but, not all lesions in the somatosensory system lead to neuropathic pain.’
CAUSE
In pediatric cancer patients, there are multiple
causes for neuropathic pain. Chemotherapeutic
agents such as vincristine, cisplatin, and paclitaxel
may cause neuropathic pain that can persist for
months or even years after therapy [4,5]. A lesion
of the spinal cord may cause pain arising as a direct
consequence of affecting the somatosensory system.
For children with malignancy, tumor-related pain as
a result of direct tissue and nerve injury can cause
significant neuropathic pain. Although this may
be transient postoperative pain, it can persist and
display clinical signs, in which we can suspect
neuropathic components. This situation is especially true for children with advanced unresectable
solid tumors, in which nerve entrapment may pose a
major problem, such as at sciatic nerve or brachial
plexus. Approximately 60–80% of adult patients
with an amputation experience phantom sensations
in their amputated limb, and most sensations
are painful [6]. Data for children have not been
published. Phantom limb pain is a complex
phenomenon that includes a wide variety of
a
Department of Pain Medicine, Palliative Care and Integrative Medicine,
Children’s Hospitals and Clinics of Minnesota and bUniversity of Minnesota Medical School, Minnesota, USA
Correspondence to Stefan J. Friedrichsdorf, MD, Children’s Hospitals
and Clinics of Minnesota, 2525 Chicago Ave S, Minneapolis, MN 55404,
USA. Tel: +1 612 813 6450; fax: +1 612 813 7199; e-mail: stefan.
[email protected]
Curr Opin Support Palliat Care 2013, 7:131–138
DOI:10.1097/SPC.0b013e3283615ebe
1751-4258 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.supportiveandpalliativecare.com
Pain: cancer
KEY POINTS
Neuropathic pain in children with cancer is common,
underrecognized, and undertreated.
There are no evidence-based recommendations treating
neuropathic pain in children with cancer.
First line medications include opioids, amitriptyline,
and gabapentin.
Rehabilitative and integrative (non-pharmacological)
therapies must be part of the treatment program.
and NIPS, are recommended and comprehensive
reviews comparing these assessment tools have been
published [11–16].
A symptom leading to the diagnosis of neuropathic pain on examination is often dysesthesia, such
as allodynia and/or hyperalgesia. However, some
children may only report paresthesia (e.g. tingling,
numbness, or ‘ants crawling on my skin’) as
their leading distressing symptom of neuropathic
dysfunction.
TREATMENT
symptoms ranging from tingling and itching to
burning and aching [7].
PAIN ASSESSMENT
Specific pain intensity scales for neuropathic pain
are currently only validated for adults and examples
include the Neuropathic Pain Scale [8,9] and the
Pain Quality Assessment Scale [10]. As a result,
neuropathic pain assessment in children often
involves tools validated for acute pain, such as
Likert-type visual analog scales (VAS), which have
been used as primary outcome measures in pediatric neuropathic pain trials. Age-appropriate tools
include one-dimensional self-report measures (e.g.,
VAS, numerical rating scales-11, or faces scales) due
to their ease of use in alert and responsive children
who are able to communicate. For infants and children under 4 years of age, there are several validated
proxy pain assessment tools available for measuring
the frequency of physical behaviors. Other well validated tools, including COMFORT, CRIES, FLACC,
There are no published randomized controlled
trials (RCTs) about the management of neuropathic
pain in children. In order to weigh benefits
and burdens of treatment strategies for children
with acute and neuropathic pain, therapies should
usually be administered along a continuum from
least invasive to most invasive (i.e. from integrative/
nonpharmacological/supportive/rehabilitative, to
topical, to enteral and parenteral administration of
medications, and finally to invasive procedures if
necessary). (See Table 1).
IDENTIFY AND TREAT THE UNDERLYING
DISEASE PROCESS
A medical examination and history is paramount
when caring for a child in neuropathic pain. For
instance, consider radiation and/or corticosteroids if
appropriate, and as always, when a child presents with
a distressing symptom, the clinician must try to identify a possible underlying disease process. The underlying cause should then be treated, if this is feasible and
within the goals of care for the child and family.
Table 1. Step-by-Step recommendations for neuropathic pain management in children with cancera
Step 1
Identify and treat underlying disease process, and consider radiation and/or corticosteroids when CNS compression appears
evident.
Step 2
Start integrative (nonpharmacological) therapies to help manage comorbidities, such as anxiety and sleep disturbance.
Step 3
Administer an opioid (plus NSAID/celecoxib, if no contraindications). Consider tramadol (for mild-medium pain) or
methadone (for medium-severe pain); however, there are no clear data that these two medications are superior to
morphine, fentanyl, hydromorphone or oxycodone.
Step 4
Add a low-dose TCA, such as amitriptyline or nortriptyline (or gabapentinoid if QTc-prolongation). These medications may
take days to start working, so consider starting low-dose ketamine as a ‘bridge’ in severe cases.
Step 5
Combine a low-dose TCA and gabapentinoid.
Step 6
If pain is localized, consider the addition of a lidocaine 5% patch (can be cut to fit).
Step 7
Begin an NMDA-receptor-channel blocker such as ketamine and or methadone, if not already administered. Depending on
the clinical picture, consider the step-wise addition of a low-dose benzodiazepine, a-agonist such as dexmedetomidine or
clonidine, and/or intravenous lidocaine.
Step 8
Consider regional anesthesia and referral to a pediatric pain specialist, if this has not already happened.
a
There are no pediatric evidence-based recommendations. The approach suggested in this table may be considered. However, it should be altered depending on
the age, underlying condition, pathophysiology, and treatment goals for the individual patient.
132
www.supportiveandpalliativecare.com
Volume 7 Number 2 June 2013
Management of neuropathic pain in cancer Friedrichsdorf and Nugent
INTEGRATIVE AND REHABILITATIVE
THERAPIES
State of the art pain management in the 21st century
demands that pharmacological management be
combined with supportive measures, rehabilitative
therapies, and integrative, nonpharmacological
treatment modalities. Common comorbidities that
are likely to worsen the neuropathic pain experience
include insomnia and/or anxiety and these comorbidities should be addressed.
Integrative, supportive, and rehabilitative therapies are an expected part of the treatment protocol.
Age-appropriate modalities include: physical
(massage, transcutaneous nerve stimulation, comfort positioning, allowing family for close contact/
touch), rehabilitation (physical therapy, occupational therapy), behavioral (deep breathing,
imagery, hypnosis, smart-phone/tablet ‘apps’), acupressure, acupuncture, and aromatherapy [17].
PHARMACOLOGIC MANAGEMENT
The following section is an overview of current
pediatric pharmaceutical pain management options,
including suggested dosing and potential side effects.
Nonsteroidal anti-inflammatory drugs
Barring obvious contraindications for NSAIDs,
clinical experience has shown that this group
of medications can be quite effective in the management of pediatric neuropathic pain. Scheduled
NSAIDs play an important role in the pharmacological approach to neuropathic pain. One might
consider a COX-2 inhibitor, such as celecoxib,
if there is a risk of bleeding-related side effects.
Ibuprofen (5–10 mg/kg PO every 6 h; dose
limit 2400 mg/day) is associated with the fewest
gastrointestinal side effects among the NSAIDs.
It should be used with caution with hepatic
or renal impairment, history of gastrointestinal
bleeding or ulcers, and it may inhibit platelet
aggregation.
Ketorolac has the advantage of intravenous
administration, but should be rotated to oral
ibuprofen as soon as it is tolerable (<2 years ¼
0.25 mg/kg every 6 h; >2 years ¼ 0.5 mg/kg every
6 h; maximum 30 mg/dose; recommended dosing
no longer than 3–5 days).
Celecoxib (a COX-2 inhibitor) may be considered if classical NSAIDs are contraindicated
(e.g., due to bleeding risk or gastrointestinal side
effects). Safety and efficacy has been established
only in children 2 years of age or older and for a
maximum of 6 months of treatment in juvenile
rheumatoid arthritis (1–2 mg/dose; maximum
100 mg every 12–24 h).
Opioids
Children with cancer with medium to severe neuropathic pain often require opioids. A review of adult
RCTs regarding drug approaches to neuropathic
pain revealed that the number needed to treat
(NNT) was 2.5 [18–20]. The NNT for tricyclic antidepressants (TCAs) was 3.6, 4.4 for lidocaine patch,
2.9–3.9 for gabapentinoids, and 6.8 for selective
serotonin reuptake inhibitors (SSRI) [16,18,21,22].
Traditional teaching that neuropathic pain is unresponsive to opioids cannot be upheld.
There is a subset of children with neuropathic
cancer pain for whom the administration of opioids
might not be indicated: children who display only
mild to medium neuropathic pain or whose pain is
well controlled alone with simple analgesia (e.g., an
NSAID/COX-2 inhibitor and an adjuvant such as
amitriptyline or gabapentin).
’Weak’ Opioids
In some pediatric patients with neuropathic pain,
particularly those with neurologic dysfunction,
tramadol might be helpful. It is a weak m-receptor
agonist, a serotonin and norepinephrine reuptake
inhibitor, and is also likely to be an a-2 agonist.
Recommended dosing is 1–2 mg/kg every 4–6 h,
maximum 8 mg/kg per day (adult 50–100 mg every
4–6 h, maximum 400 mg/day). Tramadol has been
trialed in neonates and children (mainly postoperative) and it was shown to be well tolerated
and effective [23,24]. Common adverse effects
include nausea, vomiting, dizziness, constipation,
and sedation. A rare but severe side effect is serotonergic syndrome. Tramadol does not appear to
increase the risk of idiopathic seizures, but patients
with seizure tendency or medication that lowers
seizure threshold (TCAs, SSRI, MAOI, antipsychotics), may be at increased risk.
’Strong’ Opioids
The usual starting dose for morphine in opioidnaive children older than 6 months is 0.05–
0.1 mg/kg intravenous or 0.15–0.3 mg/kg PO every
4 h titrated to effect. If dose-limiting side effects
occur, experience has shown that opioid rotation
at equianalgesic doses of fentanyl, hydromorphone,
oxycodone, diamorphine, or methadone may
improve analgesia and decrease side effects. Methadone may be a useful opioid for the management
of neuropathic pain, with its combined activity as a
m-receptor agonist, N-methyl-D-aspartate (NMDA)-
1751-4258 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.supportiveandpalliativecare.com
133
Pain: cancer
receptor antagonist, and serotonin/norepinephrine
reuptake inhibitor (see below). However, methadone
should not be prescribed by clinicians unfamiliar with
its use.
Although methadone and tramadol yield
theoretical benefit through their complementary
action in the management of neuropathic and
nociceptive pain, there are no data to support
that they are more effective than other opioids
such as morphine, fentanyl, hydromorphone, and
oxycodone.
Corticosteroids
Corticosteroids are potent anti-inflammatory agents
useful in both nociceptive and neuropathic pain.
Reducing inflammation and peritumor edema
can relieve pressure on a nerve or the spinal cord,
decrease intracranial pressure from a brain tumor, or
decrease obstruction of a hollow viscus.
Most of the complications of steroid use
(i.e., proximal muscle weakness, osteoporosis, and
immunosuppression) are long-term sequelae and
need to be carefully watched. Steroid psychosis is
a potential side effect that requires either rotation to
another corticosteroid, cessation of the drug, or
treatment with neuroleptics. Dexamethasone has
a long half-life requiring only once or twice
daily dosing. Typical doses start at 0.1–1.5 mg/kg
(maximum 4–10 mg) per day.
TCAs are the best-studied antidepressant class
that show efficacy in treating neuropathic pain.
Amitriptyline and nortriptyline, which have been
extensively studied, block reuptake of serotonin and
norepinephrine which possibly stimulates descending inhibiting pathways stemming from the periaqueductal grey, and they may also block the NMDA
receptor. In addition, opioid analgesia might be
improved with concurrent TCA administration
via a serotoninergic mechanism at the brainstem.
Adverse effects of all TCAs include arrhythmia
and anticholinergic/antihistamine effects, such as
dry mouth, constipation, urinary retention, blurred
vision, and sedation. Nortriptyline (a secondary
amine) may be better tolerated than amitriptyline
(a tertiary amine) because it has fewer anticholinergic side effects.
Dose recommendations are the same for both
amitriptyline and nortriptyline. Both are available
in liquid form and are usually started at 0.1 mg/kg by
mouth at bedtime (adult dose 5 mg) and increased to
a maximum of 0.4–0.5 mg (maximum 20–25 mg
once at night). Experience has shown that increasing beyond that dose does not appear to result in
increased analgesic effect. It may take 1–2 weeks
to titrate up to an effective dose and to determine
if the analgesic therapy is working; however,
the induction of sleep will start much sooner. An
electrocardiogram to rule out QTc-prolongation/
Wolff–Parkinson–White syndrome prior to initiation is recommended.
Adjuvant analgesia
Adjuvant analgesics are medications that, when
added to primary analgesics, further improve pain
control. Occasionally they may also be primary
analgesics. For a significant number of children with
malignancies suffering from severe neuropathic
pain, applying the World Health Organization pain
ladder (i.e., administering scheduled opioids þ/
NSAIDs/celecoxib) may not provide adequate
neuropathic pain relief, and the addition of adjuvant analgesics may be indicated.
TRICYCLIC ANTIDEPRESSANTS
There are no data that TCAs provide better analgesia
than gabapentinoids. The reason that TCAs are
often the first adjuvant include once at night dosing
options [versus three times per day (TID) for
gabapentin] and the significant sedative effect at
night, often improving insomnia. It may take days
or weeks for TCAs and/or gabapentinoids to show
their analgesic effect, so in select cases this time
period might be bridged by (or combined with)
low-dose ketamine (see below).
134
www.supportiveandpalliativecare.com
GABAPENTINOIDS
Gabapentin, and to a lesser degree, pregabalin,
are commonly used in pediatric neuropathic pain
management. There have been no pediatric RCTs
and only a few case reports published. In adults, a
recent meta-analysis showed gabapentinoids to be
efficacious in the control of neuropathic pain
of various etiologies with a NNT of 2.9–3.9 [25].
Gabapentinoids are a-2-d ligands, locking on a
voltage-gated calcium-channel at the presynaptic
nerve terminal (first neuron) at the level of the
dorsal horn, resulting in decreased release of pain
transmitters, such as glutamate, norepinephrine,
and substance P. Adult data and pediatric experience
suggest that a significant number of patients who
experience inadequate analgesia from pregabalin
benefit from gabapentin, and vice versa.
GABAPENTIN
An initial low starting dose is 2 mg/kg per dose
(maximum 100 mg/dose) once at night titrated to
6 mg/kg per dose (maximum 300 mg/dose) TID. For
Volume 7 Number 2 June 2013
Management of neuropathic pain in cancer Friedrichsdorf and Nugent
mild to medium neuropathic pain, the titration may
take up to 2 weeks to avoid side effects. For severe
pain, the titration may be significantly faster
(1–3 days), if there is no onset of distressing side
effects. If analgesia is inadequate, the dose may be
titrated in steps up to 12 mg/kg per dose (maximum
600 mg/dose) TID, then up to 18 mg/kg per dose
(maximum 900 mg/dose) TID, and finally up to
24 mg/kg per dose (maximum 1200 mg/dose) TID.
Gabapentin (as oppose to pregabalin) has a nonlinear bioavailability, meaning dose increases close
to the maximum dose may have less of an effect.
Side effects include lethargy, ataxia, nystagmus,
dizziness, thought disorder, hallucinations, headache, peripheral edema, and myalgia; these
side effects appear to be mitigated by slow dose
escalation.
PREGABALIN
Pregabalin is approved for the treatment of neuropathic pain in adults [26]. It can be used when
gabapentin is not effective or has intolerable side
effects. Safety and efficacy are not established in
pediatric patients and there is no accepted pediatric
dosing. Experience and anecdotal evidence suggests
the following for older children and teenagers:
initial starting dose 0.5 mg/kg per dose (maximum
50 mg/dose) every HS slowly titrated to 1.5 mg/kg
per dose (maximum 75 mg/dose) BID. For mild to
medium neuropathic pain the titration may take up
to 2 weeks to avoid side effects. For severe pain
the titration may be significantly faster (2–3 days).
If analgesia is inadequate, the dose may be
titrated in steps up to 3 mg/kg per dose (maximum
150 mg/dose) BID, then up to 4.5 mg/kg per dose
(maximum 225 mg/dose) BID, and finally up to
6 mg/kg per dose (maximum 300 mg/dose) BID.
Possible side effects of pregabalin include
blurred vision, life-threatening angioedema (take
precautions if prescribing angiotensin-converting
enzyme inhibitors concurrently), dizziness, somnolence, and weight gain.
There is no overall evidence of superior
efficacy for either gabapentin or pregabalin in a
meta-analysis, although the lower cost may favor
gabapentin. Conversion from gabapentin to pregabalin is around 6 : 1, meaning 300 mg gabapentin
TID (¼ 900 mg/day) equals pregabalin 75 mg BID
(¼ 150 mg/day) [19]. To avoid pain or precipitating
seizures, these anticonvulsants should be weaned
over a period of 1–2 weeks.
As mentioned above, the efficacy of TCAs
and gabapentinoids appears equal. If a single adjuvant appears ineffective and there are no contraindications in the individual child, a combination of
a medication from each group is recommended as
their mechanism of action is completely different.
TOPICAL LIDOCAINE
Experience has shown that the administration of a
lidocaine 5% patch can be beneficial, especially if
the neuropathic pain is localized. Lidocaine is a
nonselective inhibitor of sodium channels, which
have also been utilized to treat neuropathic pain.
The lidocaine 5% patch appears effective in the
management of adult neuropathic pain, including
postherpetic neuralgia, painful diabetic neuropathy,
painful idiopathic sensory polyneuropathy, nonpostherpetic peripheral neuropathies, as well as
osteoarthritis, and lower back pain. There are no
pediatric RCTs and the data are conflicting in a
recent adult meta-analysis [19]. The patch can be
cut to fit, and worn for approximately 12 h on/12 h
off. A contraindication would be severe hepatic
dysfunction. Side effects include skin problems,
such as irritation and redness.
N-METHYL-D-ASPARTATE-CHANNEL
BLOCKER
NMDA channels might commonly be involved in
the spinal neural circuitry that leads to a neuropathic pain state. At a normal resting level the
NMDA-channel is blocked by magnesium. Increased
excitation, including strong pain stimuli, may open
the NMDA channel, producing hyper excitability of
dorsal root neurons, leading to central sensitization
(i.e., amplification of neural signaling within the
CNS that elicits pain hypersensitivity), wind-up
phenomenon, and memory of pain. NMDAreceptor antagonists, such as ketamine, methadone,
and levorphanol (possibly dextromethorphane
and amantadine) – which block the channel –
can help prevent this phenomenon, leading to
decreased opioid resistance, improved hyperalgesia,
and improved allodynia.
Ketamine is an NMDA-receptor antagonist, but
it possesses other actions that may contribute to its
analgesic effect, including a m-opioid, d-opioid
and k-opioid like effect, interactions with calcium
and sodium channels, cholinergic transmission, and
noradrenergic and serotonergic reuptake inhibition.
Clinical experience has shown that ketamine is
effective for pediatric neuropathic pain in low
(i.e., sub-anesthetic) doses, either alone or, more
commonly, in combination with opioids. Ketamine
is unique among anesthetic agents in that it does
not depress respiratory and cardiovascular systems.
In low analgesic doses, the typical anesthetic-dose
side effects of ketamine (nystagmus, lacrimation,
1751-4258 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.supportiveandpalliativecare.com
135
Pain: cancer
tachycardia, and altered sensorium) are not usually
seen, though pediatric data are limited. Most
pediatric centers schedule a low-dose benzodiazepine during the ketamine administration to
avoid psychomimetic side effects. There is evidence
of significant opioid reduction in end-of-life
pediatric cancer care after the initiation of lowdose ketamine [24,27]. The advantage of ketamine
in comparison to other frequently used adjuvant
analgesia, such as anticonvulsants or antidepressants, is its immediate onset of action.
Analgesic (subanesthetic) ketamine dosing
includes the following: intravenous: 1–5 mcg/kg
per min (¼ 0.06–0.3 mg/kg per hour); PO: 0.2–
0.5 mg/kg TID–QID and PRN (as needed). Ketamine
may also be administered subcutaneously, sublingually, intranasally, or per rectum or spinally).
In the USA, ketamine is only available as a racemic
mixture [S(þ)-enantiomer (providing analgesia,
general anesthesia); R()-enantiomer (causing
bronchodilatation, nightmares)]. In most other
countries, ketamine-S [S(þ)-enantiomer] is also
available, reducing the required dose by 40–50%.
OTHER ADJUVANTS
Groups of medications, which might be considered
for refractory neuropathic pain in children with
cancer, include the following.
Benzodiazepines such as diazepam, midazolam,
and lorazepam can aid in the treatment of pain
of multiple causes; particularly when the pain is
worsened by anxiety or difficulty in sleeping.
A sodium-channel blocker that is effective for
neuropathic pain includes intravenous lidocaine.
There is limited pediatric experience in the use
of intravenous lidocaine. A case series showed it
was effective after anti-GD2 antibody therapy in
children with neuroblastoma, at a dose of 1 mg/kg
per hour [28,29]. Published dose recommendation
for lidocaine for neuropathic pain includes 1 mg/kg
over 5 min or 2 mg/kg over 30 min, then 1 mg/h target: 2–5 mcg/ml [28,30]. Side effects of intravenous lidocaine include allergic reaction (serious,
but rare), and dose-related numbness around the
mouth, dizziness, slurring of speech, hallucinations,
muscle twitches, and seizures [31].
a-2-Adrenergic agonists such as clonidine or
dexmedetomidine can be effective adjuvant analgesics for both nociceptive and neuropathic pain in
our experience. They act at the spinal cord in two
ways. First, they act on the same neurons in the cord
and lead to the same intracellular events as opioids,
but act through a different receptor; 2-adrenergic
and opioid receptors activate the same potassium
channel via inhibitory G proteins. Thus, it is likely
136
www.supportiveandpalliativecare.com
that they enhance the antinociceptive effects of
opioids. Second, a-2-adrenergic agonists decrease
sympathetic outflow involved with neuropathic
pain and hyper arousal. Clonidine can be given
orally, transdermally, or intraspinally. Side effects
include sedation, dry mouth, and hypotension.
Dexmedetomidine can also be an effective adjuvant,
leading to opioid-sparing. It carries the advantage
of not affecting respiration. However, potential
side effects include hypotension and bradycardia.
Dose recommendations: dexmedetomidine (0.3–
2 mcg/kg per hour intravenous); Clonidine (starting
dose 1–3 mcg/kg dose QHS (once a night) to every
6 h titrated to effect PO or transdermal).
SELECTIVE SEROTONIN REUPTAKE
INHIBITORSS/SELECTIVE
NOREPINEPHRINE RE-UPTAKE
INHIBITORS
Newer atypical antidepressants (e.g., selective norepinephrine re-uptake inhibitors such as venlafaxine and duloxetine) show some evidence of efficacy
for treating neuropathic pain but they have not
been well studied. In addition, there is little evidence to support their efficacy in treating pediatric
depression. Studies have shown SSRIs to be much
less effective in treating pain and are not recommended for the treatment of neuropathic pain:
Finnerup et al. [19] (2010) stated that the ‘clinical
relevance of these compounds is questionable’.
CANNABIS
Activation of the endocannabinoid system suppresses behavioral responses to acute and persistent
noxious stimulation through central and peripheral
mechanisms [32,33]. Cannabinoid receptors exist
in the periaqueductal gray area, rostral ventromedial medulla, and dorsal horn of the spinal cord.
In animal experiments, cannabinoids produce
analgesia and potentiate opioids, particularly in
neuropathic pain [34–36]. There are over 60 active
compounds extracted from cannabis. Delta-9-tetrahydrocannabinol (THC) (dronabinol, nabilone)
does not fully replicate the effect of total cannabis
preparation [37]. Cannabis sativa extract (oromucosal pump spray) is composed of both D-9-THC and
cannabidiol in a 1 : 1 ratio. Cannabis sativa extract is
approved for use in Canada for multiple sclerosis
patients with neuropathic pain [38]. Adult metaanalytic data show there is a modest effect on central
pain in multiple sclerosis (two RCTs), pain relief for
peripheral neuropathic pain (three RCTs), lack of
pain relief for polyneuropathy (one small RCT), and
superiority of smoked cannabis compared with
Volume 7 Number 2 June 2013
Management of neuropathic pain in cancer Friedrichsdorf and Nugent
placebo in HIV neuropathy (three RCTs) [19].
There are no published pediatric studies. Persistent
cannabis users show neuropsychological decline
from childhood to midlife [39] and in our clinical
practice we do not support the use of marijuana for
pain control in children and teenagers with neuropathic cancer pain, mostly because the above mentioned pharmacological and nonpharmacological
strategies seem to be effective, combined with
our clinical experience that usually teenagers with
a history of nonadherence to medical recommendations tend to request marijuana.
REVIEW OF RECENT LITERATURE
A MEDLINE search of recent publications (January
2011 to February 2013) on the topic of neuropathic
pediatric cancer pain revealed six articles; none was
an RCT.
In a retrospective analysis of 99 pediatric neuroblastoma patients with spinal cord compression,
neuropathic pain–among other distressing symptoms–was present in 56% of the cases. After a
median observation time of 8 years, 17% of the
initial group still reported impaired cutaneous sensibility and 5% reported neuropathic pain without
any clear demonstrated advantage of either first-line
neurosurgery or chemotherapy [40 ].
A retrospective, single-institution review of
pediatric cancer patients over 5 years (n ¼ 41)
reported that methadone (39% for neuropathic
pain) was effective in treating both neuropathic
and nociceptive pain that was unresponsive to other
opioids [41 ].
A case report of a 5-year-old girl who was diagnosed with meningitis caused by malignant T-cell
lymphoma and difficult to treat neuropathic pain
reported that her pain was not relieved by low doses
of a fentanyl infusion (0.8 mcg/kg per hour). Intravenous administration of lidocaine (9.3–14 mcg/kg
per minute), followed later by ketamine (2 mcg/kg
per minute) in combination with fentanyl, provided
good analgesia without significant side effects for
the last 20 days of her life [42].
A case report of a 3-year-old child with intractable trigeminal neuropathic pain caused by a
malignant glioma that was treated with resection,
followed by radiotherapy and chemotherapy, discussed successful use of motor cortex stimulation,
which provided a 75% reduction in the child’s pain
48 h postoperatively, continuing until the child was
pain-free [43].
A retrospective, single-institution review of
pediatric patients during a 26-year window revealed
a complex pain syndrome of mixed nociceptive and
neuropathic pain following limb-sparing surgery for
&&
bone cancer (n ¼ 151). Therapies included opioids,
NSAIDs, acetaminophen-opioid combinations, postoperative continuous epidural infusion, anticonvulsants, and TCAs for neuropathic pain, local anesthetic
wound catheters, and continuous peripheral nerve
block catheters [44].
A retrospective, single-institution review of
pediatric patients who presented with acute lymphoblastic leukemia during a 20-year timeframe
(n ¼ 498) revealed that 35% of the sample experienced vincristine-associated neuropathic pain. No
statistically significant relation between the severity
of the neuropathic episode and the cumulative dose
of vincristine was found. There was no evidence
gabapentin prevented recurrence of neuropathic
pain at a mean dose of 15.5 mg/kg per day. However,
as the usual maximum dose is 50–70 mg/kg per day,
that dose may have been too low to show effect [45].
CONCLUSION
There is a high prevalence of neuropathic pain
in children with cancer. Neuropathic pain is often
underassessed and undertreated with ineffective
therapies. Although there are few studies in children
to guide practice, neuropathic pain in children with
cancer can be managed through the application of
careful assessment combined with pharmacologic
and nonpharmacologic strategies. NSAIDs, opioids,
as well as gabapentin and amitriptyline/nortriptyline, are often reliable first-line agents. Integrative
and rehabilitative therapies are an essential part of a
successful treatment protocol.
&
Acknowledgements
None.
Conflicts of interest
The authors declare no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
&
of special interest
&& of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 229–230).
1. Poder U, Ljungman G, von Essen L. Parents’ perceptions of their children’s
cancer-related symptoms during treatment: a prospective, longitudinal study.
J Pain Symptom Manage 2010; 40:661–670.
2. Bennett MI, Rayment C, Hjermstad M, Aass N. Prevalence and aetiology
of neuropathic pain in cancer patients: a systematic review. Pain 2012;
153:359–365.
3. International Association for the Study of Pain. Available at: http://www.iasppain.org/AM/Template.cfm?Section¼Pain_Definitions. (Accessed 28 January
2013)
4. Dougherty PM, Cata JP, Burton AW. Dysfunction in multiple primary afferent
fiber subtypes revealed by quantitative sensory testing in patients with chronic
vincristine-induced pain. J Pain Symptom Manage 2007; 33:166–179.
1751-4258 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.supportiveandpalliativecare.com
137
Pain: cancer
5. Pace A, Carpano S, Galie E. Vitamin E in the neuroprotection of cisplatininduced peripheral neurotoxicity and ototoxicity. J Clin Oncol (Meeting
Abstracts) 2007; 25 (Suppl):abstr 9114.
6. Sherman RA, Sherman CJ, Parker L. Chronic phantom and stump pain among
American veterans: results of a survey. Pain 1984; 18:83–95.
7. Subedi B, Grossber G, Phantom Limb. Pain: Mechanisms, Treatment,
Approaches, Pain Research, Treatment 2011. [Epub ahead of print]
8. Galer BS, Jensen MP. Development and preliminary validation of a pain measure
specific to neuropathic pain: the Neuropathic. Neurology 1997; 48:332–338.
9. MAPI Research Institute. Available at: http://www.mapi-research.fr/t_03_
serv_dist_Cduse_nps.htm. (Accessed January 2013)
10. MAPI Research Institute. Available at: http://www.mapi-research.fr/t_03_
serv_dist_Cduse_pqas.htm (Accessed January 2013)
11. von Baeyer CL, Spagrud LJ. Systematic review of observational (behavioral)
measures of pain for children and adolescents aged 3 to 18 years. Pain 2007;
127:140–150.
12. Jay SM, Elliott CH, Katz E, Siegel SE. Cognitive-behavioral and pharmacologic interventions for childrens’ distress during painful medical procedures.
J Consult Clin Psychol 1987; 55:860–865.
13. von Baeyer CL, Spagrud LJ, McCormick JC, Choo E. Three new datasets
supporting use of the Numerical Rating Scale (NRS-11) for children’s selfreports of pain intensity. Pain 2009; 143:223–227.
14. von Baeyer CL. Children’s self-reports of pain intensity: scale selection,
limitations and interpretation. Pain Res Manag 2006; 11:157–162.
15. Denecke H, Hu¨nseler C. Messen und Erfassen von Schmerz. In: Schmerztherapie bei Kindern. Ed. 2. Edited by Zernikow B (editor). Berlin, Heidelberg:
Springer; 2003. pp. 51–79.
16. von Baeyer CL. Children’s self-report of pain intensity: what we know, where
we are headed. Pain Res Manag 2009; 14:39–45.
17. Friedrichsdorf S, Kuttner, L, Westendorp K, McCarty R. Integrative Pediatric
Palliative Care. In: Integrative Pediatrics. Edited by Culbert, TP, Olness K
(editors). New York: Oxford University Press; 2010 pp. 569-93.
18. Finnerup NB, Otto M, McQuay HJ. Algorithm for neuropathic pain treatment:
an evidence based proposal. Pain 2005; 118:289–305.
19. Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological
treatment of neuropathic pain. Pain 2010; 150:573–581.
20. Eisenberg E, McNicol E, Carr DB. Opioids for neuropathic pain. Cochrane
Database Syst Rev 2006; CD006146.
21. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev 2007; CD005454.
22. Wiffen PJ, McQuay HJ, Edwards JE, Moore RA. Gabapentin for acute and
chronic pain. Cochrane Database Syst Rev 2005; CD005452.
23. Bamigbade TA, Langford RM. The clinical use of tramadol hydrochloride.
Pain Rev 1998; 5:155–182.
24. Rose JB, Finkel JC, Arquedas-Mohs A. Oral tramadol for the treatment of pain
of 7–30 days’ duration in children. Anesth Analg 2003; 96:78–81.
25. Wiffen PJ, McQuay HJ, Edwards JE, Moore RA. Gabapentin for acute and
chronic pain. Cochrane Database Syst Rev 2005; CD005452.
26. Moore RA, Straube S, Wiffen PJ. Pregabalin for acute and chronic pain in
adults. Cochrane Database Syst Rev 2009; CD007076..
27. Dix P, Martindale S, Stoddart PA. Double-blind randomized placebo-controlled trial of the effect of ketamine on postoperative morphine consumption
in children following appendicectomy. Paediatr Anaesth 2003; 13:422–426.
28. Wallace MS, Lee J, Sorkin L. Intravenous lidocaine: effects on controlling pain
after anti-GD2 antibody therapy in children with neuroblastoma–a report of a
series. Anesth Analg 1997; 85:794–796.
138
www.supportiveandpalliativecare.com
29. Massey GV, Pedigo S, Dunn NL, et al. Continuous lidocaine infusion for the
relief of refractory malignant pain in a terminally ill pediatric cancer patient.
J Pediatr Hematol Oncol 2002; 24:566–568.
30. Krane E, Leong M, Golianu B, Leong Y. Treatment of Pediatric Pain with
Nonconventional Analgesics. In: Schechter N, Berde C, Yaster M, editors.
Pain in infants, children, and adolescents. Philadelphia: Lippincott Williams &
Wilkins; 2003. pp. 225–240.
31. Ferrini R, Paice JA. How to initiate and monitor infusional lidocaine
for severe and/or neuropathic pain. J Support Oncol 2004; 2:90–94.
32. Walker JM, Hohmann AG. Cannabinoid mechanisms of pain suppression.
Handb Exp Pharmacol 2005; 168:509–554.
33. Johanek LM, Simone DA. Activation of peripheral cannabinoid receptors
attenuates cutaneous hyperalgesia produced by heat injury. Pain 2004;
109:432–442.
34. Cichewicz DL. Synergistic interactions between cannabis and opioid
analgesics. Life Sci 2004; 74:1317–1324.
35. Vaughan CW, Christie MJ. An analgesic role for cannabinoids. Med J Aust
2000; 173:270–272.
36. Herzberg U, Herzberg U, Eliav E. The analgesic effects of R(þ)-WIN 55,212-2
mesylate, a high affinity cannabinoid agonist, in a rat model of neuropathic
pain. Neurosci Lett 1997; 221:157–160.
37. Williamson EM, Evans FJ. Cannabinoids in clinical practice. Drugs 2000;
60:1303–1314.
38. Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized, controlled trial
of cannabis-based medicine in central pain in multiple sclerosis. Neurology
2005; 65:812–819.
39. Meier MH, Caspi A, Ambler A, Harrington H. Persistent cannabis users
show neuropsychological decline from childhood to midlife. Proc Natl Acad
Sci U S A 2012; 109:E2657–E2664.
40. Simon T, Niemann CA, Hero B, Henze G. Short- and long-term outcome
&&
of patients with symptoms of spinal cord compression by neuroblastoma.
Dev Med Child Neurol 2012; 54:347–352.
The authors retrospectively analyzed the long-term effects of symptoms associated
with spinal cord compression in clinical trial patients with neuroblastoma. Longterm residual neurological effects are described for patients who underwent firstline neurosurgery or chemotherapy.
41. Anghelescu DL, Faughnan LG, Hankins GM. Methadone use in children and
&
young adults at a cancer center: a retrospective study. J Opioid Manag 2011;
7:353–361.
The authors of this retrospective chart review describe the effectiveness and
side effects associated with methadone use for treating children with cancerrelated neuropathic and nociceptive pain.
42. Kajiume T, Sera Y, Nakanuno R. Continuous intravenous infusion of
ketamine and lidocaine as adjuvant analgesics in a 5-year-old patient with
neuropathic cancer pain. J Palliat Med 2012; 15:719–722.
43. Delavallee M, Rooijakkers H, Koerts G, Raftopoulos C. Motor cortex stimulation in a three-year-old child with trigeminal neuropathic pain caused by a
malignant glioma in the cerebellopontine angle: case report. Neurosurgery
2011; 69:E494–E496.
44. Anghelescu DL, Oakes LL, Hankins GM. Treatment of pain in children after
limb-sparing surgery: an institution’s 26-year experience. Pain Manag Nurs
2011; 12:82–94.
45. Anghelescu DL, Faughnan LG, Jeha S, Relling MV. Neuropathic pain during
treatment for childhood acute lymphoblastic leukemia. Pediatr Blood Cancer
2011; 57:1147–1153.
Volume 7 Number 2 June 2013