Chemotherapy Induced Peripheral Neuropathy (CIPN): A Song of Ice and Fire

Chemotherapy Induced
Peripheral Neuropathy (CIPN)
A Song of Ice and Fire
Chris Ralph BSc. Pharm. FCAPhO
Complex Pain and Symptom Management Service
Tom Baker Cancer Centre
Calgary, AB
#CAPhOCon18

Disclosure
No conflicts of interest
to disclose.
Off-label medications:
Technically, all medications used
in CIPN management.

Background: How Nerves Work
More than a human electrical wiring system.
The sensors and detectors of the external and internal world
The transducers that convert information to electrical impulses
The wires that transmit the impulses
The transistors that gate information, turn up & down volume
The activators take that information and cause it to have an effect
on other organs
Nerves are bundles of cells called neurons; each neuron responsible for
one job (pain, warning, pleasure, etc.) and goes in one direction to
certain areas of the brain.

The Problem
Chemotherapy Induced Peripheral Neuropathy (CIPN):
A dose-limiting neurotoxic effect of chemotherapy
Group of neuromuscular symptoms from peripheral nerve fibres damage
& dysfunction caused by neurotoxic chemotherapeutic agents
Neuropathic pain:
Nerve pain initiated by damaged nerves, often described as sharp,
shooting, tingling, burning, cold, pins and needles

Background: Peripheral Nervous System (PNS)
The peripheral nervous system is split into 2 divisions:
● sensory (afferent)
● motor (efferent)
The PNS is made up of 43 pairs of nerves:
● 12 pairs of cranial nerves
● 31 pairs that enter the spinal cord and become the
spinal nerves

CIPN Talk Outline
Assessment
Prevention
Treatment
Magnitude
of the
Problem

CIPN Pathophysiology
● CIPN pathophysiology not
completely understood
● Results from damage to axon,
myelin sheath, or cell body
● Characterized by injury,
inflammation, or degeneration
of peripheral nerve fibres

● CIPN pathophysiology not
completely understood
● Results from damage to
axon, myelin sheath, or
cell body
● Characterized by injury,
inflammation, or
degeneration of peripheral
nerve fibres

CIPN Clinical Features
● Primarily polyneuropathy
● Symmetric stocking-glove
distribution
● Earliest symptoms developing at
fingertips & toes

CIPN Clinical Features
Hyperesthesia, contact sensitivity
Normal or knee reflexes
ankle reflexes
pin, temperature, vibration
or normal strength

Patient Symptoms
Numbness Tingling
Burning
Shooting
Throbbing
Stabbing
Schloss J, APJON 2016

CIPN Assessment
Subjective
Symptoms:
● Sensory
● Motor
● Autonomic
Objective:
● Touch, pinprick, vibration, proprioception
● Reflexes, muscle strength, gait, balance
● Autonomic: bowel sounds, orthostatic BP, pulse
● Fine motor skills: buttoning clothes, opening jars

Patient Symptoms
Sensory Nerves
● Tingling, burning, numbness, or a "buzzing" sensation
○ starts in the toes and fingers, moves to hands & feet, then towards the centre of the body
● The feeling that one is wearing tight gloves or stockings
● Allodynia:
○ Pain when bedding, clothes, socks, shoes, or anything touches the skin
● Sudden stabs or burning pains; pinching; "electrical" shock-type pain
● Thermal hyper- or hyposensitivity to stimuli
(exacerbation in cold weather; inability to remove items from the fridge)
● Loss of proprioception

Patient Symptoms
Motor Nerves
● Mechanical hyper- or hyposensitivity to stimuli
(pain on walking/moving)
● Arms and legs may feel heavy or weak
○ coordination and balance problems
● Difficulty in using hands and arms
● Difficulty with fine motor movements
(e.g. buttoning a shirt or using a cell phone)
● Experiencing muscle cramps in the hands and feet

Patient Symptoms
Autonomic Nerves
● Heat intolerance and altered sweating
● Bowel, bladder or digestive problems
● Changes in blood pressure causing dizziness or lightheadedness
● Trouble swallowing
● Sexual problems

CIPN Impact on Health QOL
Associated with psychological disorders:
● Depression
● Anxiety
● Sleep difficulties
Poupon, Expert Opin. Drug Saf. 2015

CIPN Economic Burden
Average to a patient’s health cost:
,
Poupon, Expert Opin. Drug Saf. 2015

Person with CIPN 1.8
times the risk of falls
Winters-Stone, JOCO 2017

CIPN Prevalence
Per cent when measured after chemotherapy:
in first month
after 3 months
after 6 months
Seretny M, Pain 2014

CIPN Contributing Factors
30-70%
CIPN
Incidence
Anticancer
medication
Treatment combinations,
dose accumulation
Other factors
Dose
Preet G, PLOS One 2017

CIPN Contributing Factors
30-70%
CIPN
Incidence
Peripheral neuropathy
from comorbidity
Surgical trauma
Paraneoplastic
syndrome
Tumour infiltration
and compression
Preet G, PLOS One 2017

CIPN ?Risk Factors*
● Genetic risk factors (some SNPs identified)
● History of neuropathy (e.g. diabetes)
● Impaired renal function
● Vitamin B12 deficiency
● History of smoking
● Alcoholism
● Genetics
● HIV
*Much more work needed in this area
Flatters, BJA 2017

CIPN Genetic Factors
Vincristine
75% of 20 patients homozygous for CEP72 T allele developed grade 2-4
neuropathy, compared to 44% of patients with CEP72 CC or CT genotype
(P = 0.0221).
The CEP72 polymorphism can identify adults at increased risk of vincristine-
induced peripheral neuropathy.
Because leukemia cells of patients with the CEP72 T/T genotype are more
sensitive to vincristine, it may be feasible to treat these patients with a lower
dosage of vincristine.
Stock, Clin Pharmacol Ther. 2017

Neurotoxic Offending Agents
Medication Incidence Onset Dose Clinical Features Recovery
Cisplatin
28-100% (overall)
+ paclitaxel: 7-8% severe
300 mg/m2
Symmetrical painful paraesthesia or
numbness in a stocking-glove distribution,
sensory ataxia with gait dysfunction
Partial, symptoms may
progress for months after
discontinuation
Carboplatin
6-42% (overall)
+ paclitaxel: 4-9% severe
800-1600
mg/m2 Similar to cisplatin but milder Similar to cisplatin
Docetaxel
11-64% (overall)
4-14% (severe)
75-100 mg/m2 See paclitaxel
Resolution usually within 3
months; may persist
Oxaliplatin
(acute)
85-95% (overall) any Cold-induced painful dysesthesia Resolution within a week
Oxaliplatin
(persistent/
chronic)
10-18% (FOLFOX severe)
750-850
mg/m2 Similar to cisplatin
Resolution in 3 months; may
persist long-term
Paclitaxel
57-83% (overall)
2-33% (severe)
100-300
mg/m2
Symmetrical painful paraesthesia or
numbness in a stocking-glove distribution,
↓ vibration or proprioception,
sensory ataxia with gait dysfunction
Resolution usually within 3
months; may persist
Nab-paclitaxel
(AbraxaneⓇ)
11-64% (overall)
4-14% (severe)
unclear Similar to paclitaxel
Resolution usually
within 3 weeks

Neurotoxic Offending Agents: Hematology
Medication Incidence Onset Dose/Time Clinical Features Recovery
Bortezomib
31 to 45% (overall)
5–16% (severe)
less with SC
(38% SC vs. 53% IV)
~30 mg/m2
Plateau: 42-45mg/m2
Neuropathic pain (fingertips & toes), sensory
loss to all modalities, distally attenuated,
suppression or even abolishment of deep
tendon reflexes in proportion to sensory loss
and proprioception changes.
85% of patients 2-3.5
months after
discontinuation;
30 % do not recover
Carfilzomib
5-14% (overall)
1% (severe)
no cumulative
neurotoxicity
n/a n/a
Brentuximab
vedotin
Sensory:
52-53% (overall)
8-10%(severe)
Motor:
7-16% (overall)
3-4%(severe)
Clinically significant
PN ↑ing by 23% for
each 100 mg increase
in total dose
Distal numbness, though often subtle.
Functional complaints, including tactile
changes in hands & changes to gait usually
more prominent. Distal vibratory sensory
loss most prominent finding on exam.
Resolution usually
within 7-30 weeks; 74%
had improvement by
24 months
Lenalidomide
6-28% (overall)
<1% (severe)
No correlation Sensory neuropathy; long-term therapy with
lenalidomide is associated with frequent, but
mild and subclinical, peripheral neuropathy.
*long-term therapy
associated with mild,
subclinical CIPN
Pomalidomide
12-18% (overall)
1% (severe)
Median time:
1.7 months
n/a n/a
Vincristine
78% (overall)
(?) % (severe)
4 mg/m2 Distal numbness, tingling; motor, sensory,
autonomic fibers affected. Distal weakness
may occur rapidly & limit further treatment.
Resolution usually
Within 3-5 months

CIPN Assessment: Evaluation & Tests
Electrodiagnostic:
● Electromyography (EMG)
● Nerve conduction velocity test (NCV)
Other:
● Quantitative sensory testing (QST)
● Autonomic testing
Blood tests:
● Vitamin B12 and folate levels
● Thyroid, liver and kidney functions
● Vasculitis evaluation
● Oral glucose tolerance test
● Antibodies to nerve components
(e.g., anti-MAG antibody)
● Antibodies related to celiac disease
● Lyme disease
● HIV/AIDS
● Hepatitis C and B

CIPN Assessment
A diverse range of CIPN assessments currently exists. While several assessments assess CIPN symptoms with adequate
comprehensiveness, depth, language, and feasibility, the consensus ‘gold standard’ clinical assessment remains to be established. (26)
Considering the psychometric properties and practicality, two tools (Functional Assessment of Cancer Therapy/Gynecologic Oncology
Group-Neurotoxicity [FACT/GOG-Ntx] and Total Neuropathy Score [TNS]) are recommended for assessing CIPN. (25)
...the CTCAE grading system for CIPN lacks granularity, relies heavily on patient report, and often over-emphasizes “positive
symptoms,” such as tingling and pain, while missing “negative” symptoms, including loss of sensation or balance trouble. We adopted
the TNSc as a more sensitive instrument to capture the development of PN. The most prominent clinical exam finding in this study was
almost always vibratory sensory loss, which is captured in this score and often missed otherwise. (52)
Clinical tests like nerve conduction tests and electromyography that are routinely used to assess neuropathy are insensitive during early
stages even when the patients may be showing signs of motor or sensory neuropathy. Nerve conduction velocity (NCV) measures
velocity and amplitude in the large diameter and fast conducting fibres and thus does not provide reliable data on the small fibres. NCV
may reflect the status of surviving fibres and may not identify the state of the fibres affected. (33)

CIPN Assessment
A diverse range of CIPN assessments currently exists. While several assessments assess
CIPN symptoms with adequate comprehensiveness, depth, language, and feasibility, the
consensus ‘gold standard’ clinical assessment remains to be established. (26)

CIPN Assessment
Considering the psychometric properties and practicality, two tools (Functional Assessment
of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity [FACT/GOG-Ntx] and
Total Neuropathy Score [TNS]) are recommended for assessing CIPN. (25)

CIPN Assessment
...the CTCAE grading system for CIPN lacks granularity, relies heavily on patient
report, and often over-emphasizes “positive symptoms,” such as tingling and pain,
while missing “negative” symptoms, including loss of sensation or balance trouble. We
adopted the TNSc as a more sensitive instrument to capture the development of PN.
The most prominent clinical exam finding in this study was almost always vibratory sensory
loss, which is captured in this score and often missed otherwise. (52)

CIPN Assessment
Clinical tests like nerve conduction tests and electromyography that are routinely used to
assess neuropathy are insensitive during early stages even when the patients may be showing
signs of motor or sensory neuropathy. Nerve conduction velocity (NCV) measures velocity
and amplitude in the large diameter and fast conducting fibres and thus does not provide
reliable data on the small fibres. NCV may reflect the status of surviving fibres and
may not identify the state of the fibres affected. (33)

CIPN Assessment
● Unless painful, patient difficulty describing uncomfortable sensations
● Perception that CIPN is a minor problem that eventually resolves
● A clinician/patient-friendly, useful, comprehensive tool not yet developed
● The level of toxicity subjectively determined by the clinician
Problems, Challenges, and Limitations

CIPN Assessment: Patient Story + Exam
Most reliable method of detection:
Detailed patient history
Neurological examination
Impairments of:
● Vibration
● Proprioception
● Two-point
discriminatory
sensations

Monitoring CIPN
MAPSS
Mood
Sleep Symptoms
Activity
Pain

“Life is like riding a bicycle. To keep your balance, you must keep moving.” - Albert Einstein

CIPN Prevention
"CIPN is a substantial clinical problem,
there is no good prevention of it
except to not give the drug
or to decrease the dose..."
Charles Loprinzi, MD
(professor of breast cancer research, Mayo Clinic, Rochester, Minnesota)

CIPN Prevention
● No established agents recommended for CIPN prevention
● This is based on the paucity of high-quality, consistent evidence, and a
balance of benefits versus harms.
Hershman, JCO 2014

CIPN Prevention:
Clinicians should NOT offer the following agents for the prevention of CIPN to
patients with cancer undergoing treatment with neurotoxic agents:
● Acetyl-l-carnitine (ALC)
● Amifostine
● Amitriptyline
● CaMg for patients receiving oxaliplatin-based chemotherapy
● Diethyldithio-carbamate (DDTC)
● Glutathione (GSH) for patients receiving paclitaxel/carboplatin chemotherapy
● Nimodipine
● Org 2766
● All-trans-retinoic acid
● rhuLIF
● Vitamin E
Hershman, JCO 2014

Acetyl-L-carnitine (ALC): A Cautionary Tale
Background: In mitochondria, it ensures availability of acetyl-CoA for elimination of toxic metabolic
products, is involved in acetylation of proteins including tubulin that play a role in neuronal protection.
Study: Double-blind RCT compared efficacy of oral acetyl-L-carnitine 3,000 mg daily for 24 weeks with a
cellulose placebo capsule in women undergoing adjuvant taxane-based chemotherapy
Purpose: CIPN prevention as the primary endpoint was measured using the 11-item neurotoxicity
component of the Functional Assessment of Cancer Therapy-Neurotoxicity/Taxane scale at 12 weeks.
Results: Despite evidence from preclinical and phase II studies indicating that acetyl-L-carnitine may be
effective for both treatment and prevention of taxane-induced PN symptoms, investigators in this large
RCT found no evidence of CIPN prevention at 12 weeks (the primary endpoint)
ALC actually CIPN and functional status at 24 weeks.
Brami, Crit Rev Oncol Hematol, 2016

“The first principle is that
you must not fool yourself
and you are the easiest
person to fool.”
- Richard P. Feynman
(scientist, 1918-1988)

CIPN Prevention: “Venlafaxine NOT recommended
...for routine use in clinical practice. Although initial venlafaxine data support its
potential utility, the data were not strong enough to recommend its use in clinical
practice, until additional supporting data become available.”

CIPN Prevention: Venlafaxine update
● A pilot randomized, placebo-controlled, double-blind study
of venlafaxine to prevent oxaliplatin-induced neuropathy
● Purpose: obtain data to support conducting a phase III trial
● Method: 50 patients, scheduled to undergo FOLFOX for
stages II-III (67%) or stage IV (33%) colon cancer, were
randomized to receive:
○ venlafaxine XR (37.5 mg) or placebo BID
○ through their last dose of oxaliplatin & then titrated off
○ Neurotoxicity evaluation: EORTC QLQ-CIPN20
instrument & others
Zimmerman, Supp Care Ca 2016

CIPN Prevention: Venlafaxine update
Results:
● Suggestion of some small benefit for venlafaxine when evaluated by the Oxaliplatin Specific
Neurotoxic grading scale and acute neuropathy measures of (1) discomfort swallowing cold liquids
and (2) throat discomfort, for the first 2 oxaliplatin doses.
● Positive trends outweighed by lack of any such trends in other measurements, including:
○ the EORTC QLQ-CIPN20 sensory, motor, or autonomic neuropathy subscales
○ any of the individual items of the EORTC QLQ-CIPN20 tool
○ the NCI CTCAE tool
○ the evaluations of the doses of oxaliplatin that were able to be administered
○ the bulk of the acute neuropathy data
In fact, some of these other items tended to favor the placebo arm
Conclusion: the current study does NOT support the conduct of a larger phase III trial to
investigate use of venlafaxine for the prevention of oxaliplatin-induced peripheral neuropathy.
Zimmerman, Supp Care Ca 2016

CIPN Prevention: Minocycline
Background: extensive animal data suggest that minocycline may prevent CIPN.
Minocycline crosses BBB, neuroprotective in experimental animal models of neurological injury and
neurodegenerative disease
Purpose: investigate efficacy of minocycline for Px of CIPN & acute pain syndrome (P-APS) in paclitaxel
Method: 47 Patients with breast cancer - weekly paclitaxel for 12 weeks
● randomized to receive minocycline 200 mg on day 1 followed by 100 mg twice daily or a placebo.
● Patients completed:
○ (1) an acute pain syndrome questionnaire daily during chemo
○ (2) EORTC QLQ-CIPN20 questionnaire at baseline, prior to each dose, & monthly for 6
months post treatment
Pachman, Supp Care Ca 2017

CIPN Prevention: Minocycline
Results:
● No remarkable differences between minocycline & placebo groups for overall
sensory neuropathy score of the EORTC QLQ-CIPN20 or its individual components,
which evaluate tingling, numbness and shooting/burning pain in hands and feet
● However, patients taking minocycline had a significant reduction in the daily
average pain score attributed to P-APS (p = 0.02).
● Not only were no increased toxicities reported with minocycline, but there was a
significant reduction in fatigue (p = 0.02).
● Further study of the impact of this agent on those endpoints may be warranted.
Pachman, Supp Care Ca 2017

CIPN Prevention: Vitamin D
● Prospective open case–control study in 70 patients
undergoing paclitaxel chemotherapy
● CIPN complication in 60%
● Vitamin D levels (p = 0.008):
○ group without CIPN estimated to be 38.2 (24.95, 47.63) nmol/L
○ group with CIPN determined to be 25.6 (19.7, 32.55) nmol/L
○ Samples taken at start, 4th and 12th cycles
● Supplementation of vitamin D before chemotherapy could
be an efficient neuroprotective in CIPN prophylaxis
Grim, Nutrients 2017

CIPN Prevention: Other Agents
At this time, no recommendations can be made on the use of:
● N-acetylcysteine
● carbamazepine
● Glutamate
● GSH
● goshajinkigan (GJG)
● omega-3 fatty acids
● oxcarbazepine

CIPN Prevention: Cryotherapy
Non-pharmacological modality
● Study: 44 patients were enrolled in prospective trial
○ 36 evaluable for analysis at study endpoint.
● Intervention:
○ Each patient wore frozen flexible gloves & socks [Elasto-Gel, Akromed] on
dominant hand & foot from 15 minutes before paclitaxel administration
to 15 minutes after infusion complete.
○ The nondominant side acted as the untreated control.
○ Symptoms of CIPN also assessed when patients reached a cumulative
treatment dose of 960 mg/m2 — the dose recommended for both
neoadjuvant & adjuvant weekly paclitaxel therapy.
○ 25/36 evaluable participants reached the cumulative dose of 960 mg/m2,
while another 11 patients received even higher doses
Grim, JNCI 2017

CIPN Prevention: Cryotherapy
● Primary endpoint: incidence of CIPN (any grade)
○ defined as a decline in tactile sensation from the pretreatment baseline as assessed by the
Semmes-Weinstein monofilament test
○ This test is the most widely used test to diagnose the loss of protective sensation, one
component of CIPN.
● Results:
○ On the dominant side, where patients had been treated with cryotherapy, 27.8% of hands
had detectable tactile deterioration — the definition of CIPN for the study
○ compared with 80.6% of untreated hands (P < .001).
○ Similarly, 25% of feet treated with cryotherapy had evidence of tactile deterioration at study
endpoint compared with 63.9% of untreated feet (P < .001).”
○ “Our (larger study) trial should be reported at ASCO 2018, and hopefully we will see enough
information about cryotherapy in CIPN by then that will allow us to proceed with it.”
- Dr Loprinzi

CIPN Prevention: Other Useful Measures
In Patients treated with...
Oxaliplatin:
● Limit cold exposure
● Stopping &
reintroducing
● Lengthening infusion
duration
Bortezomib:
● Weekly vs twice weekly
treatment schedules
● Subcutaneous
administration
Vincristine:
● Prophylactic laxative(s)
(PEG-3350 ± Senokot)
due to high incidence of
constipation

CIPN Pharmaceutical Treatment
For patients with cancer experiencing CIPN, clinicians may offer duloxetine.
These agents may be offered on the basis of data supporting their utility in other
neuropathic pain conditions given the limited other CIPN treatment options:
● Tricyclic antidepressants (TCA; e.g. nortriptyline)
● Gabapentin
● BAK gel: compounded topical containing baclofen (10 mg),
amitriptyline HCL (40 mg), and ketamine (20 mg)
Hershman, JCO 2014

CIPN Treatment: Duloxetine, A Closer Look
Study:
Multicenter randomized double-blind crossover trial involving 231 patients with
taxane- or platinum-associated CIPN.
Method:
Patients randomly assigned to receive duloxetine (30 mg daily for 1 week, then 60
mg daily for 4 weeks) or placebo for 5 weeks, followed by washout period, then a
crossover to opposite arm.
Hershman, JCO 2014

Results:
Patients who received duloxetine as initial therapy experienced a mean decrease in
average pain of 1.06, compared with 0.34 for those receiving placebo (a reduction
of 0.72; P = .003), as measured by the Brief Pain Inventory–Short Form.
Hershman, JCO 2014
Adverse Effects:
● Associated with fatigue and nausea
● Dropout rate of 12%
of those who received duloxetine experienced in pain of any amount
of those who received placebo experienced in pain of any amount

Duloxetine only drug with RCT evidence of benefit for CIPN
Key trial predominantly included patients with breast & GI malignancies with
grade 1 or higher sensory neuropathy & ≥ 4/10 average chemotherapy-induced
pain 3 or more months after treatment completion.
Exploratory subgroup analysis suggests that duloxetine may work better for
oxaliplatin-induced, as opposed to paclitaxel-induced, painful neuropathy.
Hershman, JCO 2014

Duloxetine trial secondary analysis:
Higher baseline emotional functioning predicted greater pain reduction. One
proposed theory was that stress and anxiety exacerbate CIPN symptomatology.
Thus, treatment of coexisting emotional distress is important for optimizing
management of the painful neuropathy.
Kim, Curr Opin Anaesthesiol. 2017

Predictive factors of usefulness of duloxetine
From retrospective study:
● body height (low)
● history of docetaxel use (less)
● site of symptom (upper limb)
Regarding the site of symptom(s):
● More effective for CIPN in upper limbs.
● This may be related to the weight-bearing ability of lower limbs.
● Clinicians shuld be aware CIPN in lower limbs may be more difficult to treat.
Kanbayashi Med Oncol. 2017

CIPN Treatment: A Song of Ice and Fire
Menthol Versus Capsaicin
Fallon Supp Care Oncol. 2015
● Binds to TRPM8 receptors
(itch, light touch)
● Sends a cooling, non-pain
signal along damaged
pathway
● Apply BID to affected area
and low back
● Not harmful!
● 82% improvement (31/38) in total Brief Pain Inventory
scores
● 50% clinically relevant reduction in pain scores of ≥ 30 %
● Reduced area of hypersensitivity
● Significant improvements also seen in:
○ Mood
○ Walking
○ Catastrophizing
● No significant improvement in hand dexterity
● Higher % not necessarily better, but what’s the cutoff?

CIPN Treatment: A Song of Ice and Fire
Menthol Versus Capsaicin
● Agonist of transient receptor potential vanilloid receptor (TRPV1)
● Inhibits neural transmission in sensatory axons
● Topical capsaicin 8% patch (USA)
○ Proven effective for post-herpetic neuralgia and (HIV)-associated neuropathy
● Large Cochrane Database review suggests should be used only as last resort
● In 12-week study in 18 oxaliplatin patients, total reduction of pain ranged
between 84% & 97% assessed at 12 weeks
● No adverse events observed
● High-dose capsaicin potential safe and effective way to treat CIPN.
Filipczak-Bryniarska Med Oncol. 2017

CIPN Treatment: A Cautionary Tale
Alpha lipoic acid (ALA)
● Reasonable to trial for diabetic neuropathy.
● Anecdotally, patients report makes them feel better
● Potentially, theoretically modifies the neuropathy
● Some suggest could try it for few months to evaluate
● BUT...

CIPN Treatment: A Cautionary Tale
Alpha lipoic acid (ALA)
● Exposure of cells to ALA alone had stimulatory effect on
growth of MM cell lines in vitro.
● ALA significantly efficacy of BTZ (about 30%).
● ALA significantly reduced BTZ-mediated endoplasmic
reticulum stress as measured by reduction in BiP1 and
IRE1α, ERO1α, and PDI expression.
● Even if no interaction/caution listed in a natural medicines
database, does NOT mean that there isn’t one.
Steinberg, Blood 2009
Tibullo, Mol Neurobiol 2017

CIPN Nonpharmacological Modalities
“The paucity of RCT evidence prohibited inclusion of the studies on the
number of nonpharmacologic interventions that have been investigated for their
role in preventing or treating peripheral neuropathy in this systematic review.”
Hershman, JCO 2014

CIPN Nonpharmacological Modalities
Physical therapy: assist balance, strength and safety
(ultrasound being explored)
Occupational therapy: help with fine motor skills
(e.g. buttoning shirts)
Exercise: up next…
Acupuncture: safe method of neuromodulation;
evidence inconclusive
Electroencephalogram (EEG) neurofeedback (NFB):
mean decrease in average pain with NFB was 2.2 points

CIPN Treatment: The Exercise Prescription
Significant improvements were detected on postural control. Additionally, patients' quality of life and
independence were found ameliorated after exercise sessions. Combined exercise protocols including
endurance, strength and sensorimotor training showed larger improvements. [Duregon 2018]
This is the first investigation showing positive effects of a multimodal exercise program on CIPN, balance
and strength on mCRC patients in a palliative setting, thereby consequently increasing patients` quality of
life. The results support earlier findings stating a positive influence of balance exercise on CIPN.
[Zimmer 2018]
Exercise reduced CIPN symptoms of hot/coldness in hands/feet (-0.46 units, p = 0.045) and numbness
and tingling (- 0.42 units, p = 0.061) compared to the control. Clinicians should consider prescribing
exercise for these patients. [Kleckner 2017]

Significant improvements were detected on postural control. Additionally,
patients' quality of life and independence were found ameliorated after
exercise sessions. Combined exercise protocols including endurance, strength and
sensorimotor training showed larger improvements. [Duregon 2018]
[Zimmer 2018]

This is the first investigation showing positive effects of a multimodal exercise
program on CIPN, balance and strength on mCRC patients in a palliative
setting, thereby consequently increasing patients` quality of life. The results
support earlier findings stating a positive influence of balance exercise on CIPN.
[Zimmer 2018]

[Zimmer 2018]
Exercise reduced CIPN symptoms of hot/coldness in hands/feet (-0.46 units,
p = 0.045) and numbness and tingling (- 0.42 units, p = 0.061) compared to
the control. Clinicians should consider prescribing exercise for these patients.
[Kleckner 2017]

6 weeks of exercise during chemotherapy—compared to chemotherapy without
exercise—reduced the prevalence and severity of CIPN symptoms, as assessed by
patient reports of numbness and tingling and hot/coldness in hands/feet.
[Kleckner 2018]

CIPN Treatment
Future Directions

Topical gabapentin
Most centres use 6% w/w gabapentin, compounded, applied TID
Reported to relieve the pain of vulvodynia, PHN, other local pain problems
In recent series, 20 of 23 benefited, with pain scores falling from 8.2 to 5.6 at 1 month, and
11 of 23 achieving a clinically meaningful 30% reduction in pain.
Penetrates deep enough to affect local nociception
Typical side effects associated with PO gabapentin (sedation, fatigue, and edema) minimal,
since application even to a large area would result in absorption of only ~ 100 mg/day.
Hiom, British J Dermatol. 2015

Other Topicals
● Topical lidocaine 5% patch
○ Used on the feet, under the stocks
○ If no skin reaction, leave on 24 hrs
○ Can take up to 4 weeks to work
○ Used as an adjunct
○ No major studies underway as of yet
○ Patch formulation only in USA
○ ?Try cream/ointment/gel
● Topical morphine gel
○ Opioid receptors are upregulated in
nerve injury
○ Avoid systemic opioid adverse effects
○ Compounded:
■ 20 mg in 10 mLs of Instillagel
Mohamed, Reg Anesth Pain Med 2016Kim, Eur Rev Med Pharmacol Sci. 2017

Intriguing Potential Treatment
Intravenous lidocaine
Study:
Small observational of only 9 patients
Results:
8/9 patients exhibited analgesic effect and derived clinically significant benefit
(>30% pain intensity difference)
It also seemed to decrease pain for an average of 23 days for 5/9 of these patients.
Suggests lidocaine infusions should be considered more frequently in Tx of refractory CIPN.

Cannabis
Both CBD and THC alone attenuated mechanical allodynia in mice treated with paclitaxel.
Very low ineffective doses of CBD and THC were synergistic in combination.
CBD oxaliplatin- but not vincristine-induced mechanical sensitivity
THC significantly vincristine- but not oxaliplatin-induced mechanical sensitivity.
Low dose combo oxaliplatin- but not vincristine-induced mechanical sensitivity.
CBD may be potent & effective at prevention of CIPN; its clinical use may be enhanced by co-
administration of low doses of THC.

Neuromodulation: Scrambler therapy
● Delivers an alternative “non-pain” signal to damaged nerve pathways
● Evidence is still limited
● TENS may work for superficial pain but has not been used successfully for
CIPN or serious cancer pain.
● Scrambler therapy (Calmare): Smith et al:
○ Pain relief in 16 of 18 patients with refractory CIPN
○ In 4, pain resolved to 0/10 & overall average in pain of ~60%
● Function improved in most patients, including less interference with
walking & sleeping ≥ 3 months.
● Pachman et al at Mayo Clinic replicated this study
○ reported ~ 50% reduction in pain, numbness & tingling ≥ 3 months
● No harm in any trial of scrambler therapy
● Mayo Clinic RCT study: Scrambler Vs TENS in CIPN
○ Estimated time to completion Aug 2021
Pachman Supp Care Ca. 2015

Virtual Reality (VR)
Dr. Brennan Siegel, Cedars-Sinai hospital
has conducted clinical trials that show a
pair of 3-D goggles can reduce the
experience of pain—all kinds, from joint
injuries to cancer—by a quarter.
20 minutes can have drastic effect
Use games like Bear Blast, SnowWorld
Experiences, like swimming with dolphins
or flying over the fjords of Iceland, or just
sitting on a beach and thinking about life
Molteni, Wired.com, Nov. 2017

CIPN Prevention Potentials
lithium and ibudilast
Administered as a single prophylactic injection prior to paclitaxel treatment,
prevent the development of CIPN in mice at the sensory-motor & cellular level
● Allows for administration of higher doses of paclitaxel (survival by 60%)
● Protects against paclitaxel-induced cardiac abnormalities
● Does not interfere with the antitumor effects of paclitaxel
Mo, FASEB J. 2012

HDAC6 inhibition effectively reverses CIPN
● ACY-1215 (Ricolinostat) not FDA/Health Canada approved
● Pharmacological inhibition of HDAC6 completely reverses all the hallmarks
of established cisplatin-induced peripheral neuropathy (in mice) by:
○ normalization of mitochondrial function in dorsal root ganglia and nerve
○ restoration of intraepidermal innervation
● Especially promising in clinical trials as add-on cancer therapy:
○ At the recommended phase II dose of ricolinostat of 160 mg daily, the combination with
bortezomib and dexamethasone is safe, well-tolerated, and active, suggesting that selective
inhibition of HDAC6 is a promising approach to multiple myeloma therapy.
Vogl, Clin Cancer Res. 2017
Krukowski, Pain 2017

Proposed
CIPN Treatment
Approach

Suggested CIPN Treatment Approach
Duloxetine
TCA (nortiptyline)
Gabapentin
Topical BAK gel
Pregabalin
Opioid (systemic)
Menthol 1%
aqueous cream
Topical
gabapentin 6%
Topical morphine
Methadone
Buprenorphine
Topical anesthetic
(lidocaine)
Nabilone Exercise
Physical therapy
Occupational
therapy
Acupuncture
Scrambler therapy
Nabiximols
Neurofeedback
Topical capsaicin
Tapentadol
Tramadol
Goal of medication: pain, symptoms by ≥ 30%, improve functioning, mood, sleep.
If no benefit after adequate trial with first intervention or not tolerated, discontinue.
If partial benefit, add additional agent sequentially, especially for intractable pain.
May require 2-4 agents of different mechanisms of action.
Cannabis
IV Lidocaine

CIPN Treatment: Pharmacological Options
Medication Dosing Evidence Risk-Benefit Comments
duloxetine
30 mg PO daily x
1/52 then 60 mg
daily
High
0.72 point reduction on 0-10 pain scale;
manageable adverse effects
Only drug with
RCT evidence of
established benefit
TCA (e.g.
nortriptyline)
10-25 mg PO HS;
increase by 10 mg
q2-3 as tolerated
up to 50-100 mg
HS
Moderate
Weak evidence in CIPN. 0.5-1.5 reduction in
pain in other studies in neuropathic pain
Use with caution in
elderly; monitor
drowsiness, constipation,
urinary retention, dry
mouth, confusion
gabapentin
100 mg PO TID or
300 mg HS;
increase by 300 mg
daily q3d up to
600 mg TID
Moderate As above
Monitor drowsiness,
dizziness, peripheral
edema, blurred vision
pregabalin
75 mg PO BID;
increase by 75 mg
BID q7d up to
300 mg BID
Moderate As above As above
Opioid
(morphine,
oxycodone,
hydromorphone,
fentanyl)
Morphine
equivalents: 10-15
mg SR PO BID;
titrate to lowest
effective dose
Moderate
Sometimes only medication to provide relief
but CIPN can be resistent; predictable
adverse effects
In setting of chronic pain,
current guidelines suggest
lowest effective dose;
discontinue if no
improvement in function

CIPN Treatment: Topical Pharmacological Options
Medication Dosing Evidence Risk-Benefit Comments
Topical
BAK Gel
Apply to affected
area BID
Randomized trial
showed no harm,
small benefit
Minimal risk; may help more on hands
than feet due to penetration
baclofen (10 mg),
amitriptyline HCL (40
mg), & ketamine (20 mg);
trials with higher
concentration needed
Topical
menthol 1%
aqueous
cream
Apply to lower back
and affected
area BID
One phase II trial and
case reports;
randomized trials
underway
No harm; inexpensive; may help more on
hands than feet due to penetration
Do not use 10% menthol
as may reinforce
pain signal
Topical
gabapentin 6%
cream
Apply to affected
area TID
Phase II trials; none
specific to CIPN
Minimal risk; all patients who have
responded did so within one hour
of application
Avoids systemic and CNS
adverse effects
Topical
lidocaine 5%
Patch: if no skin
reaction, leave on
24 hrs.
Cream/Oint: BID-TID
RCTs, observational
studies in other
neuropathic pain;
none in CIPN
Useful as adjunct; can take up to
4 weeks to work
Can take up to 4 weeks to
work; patch n/a in
Canada; other anesthetic
agents worth exploring
like bupivacaine
Topical
morphine gel
Apply TID-QID
20 mg in 10 mLs of
Instillagel
Case reports as topical
in head and neck
cancer patients
Can provide analgesia for 7–8 hrs; opioid
receptors are upregulated in nerve injury;
avoid systemic opioid adverse effects
Other opioids worth
exploring such as
methadone

Summary & Take Home Messages
Paucity of evidence to support any preventative measures
Match treatments to patient’s goals. Listen. Be empathetic.
Do what we can, with what we currently have.
Keep eyes and ears open for better options, and opportunities to
further the much needed research in this area.
Duloxetine: best evidence for treatment, but effect is limited.

Connect
@ChrisRalphRx
@ChrisRa1ph
bit.ly/chrisralphrx
cralph@ualberta.ca

Which of the following has not
been shown to be helpful in CIPN?
1. Argentine Tango
2. Sweet bee venom pharmacopuncture
3. Tart cherry juice
4. Lithium
5. Jedi training lightsaber exercises (Star wars)

Chemotherapy Induced Peripheral Neuropathy (CIPN): A Song of Ice and Fire

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