7.15 (13.3) Management issues in neuropathic pain

Question 1

Define neuropathic pain

Answer 1

Heterogenous group of chronic pain conditions arising from a lesion or disease of the peripheral or central somatosensory nervous system

Question 2

List four etiologies of peripheral neuropathic pain.

List four etiologies of central neuropathic pain

Answer 2

Peripheral:
Mononeuropathy (DM, EtOH, HIV, chemo) plexopathy
radiculopathy
nerve injury (post-sx, post-traumatic)
amputation
root avulsion
PHN
trigeminal neuralgia
neoplasm

Central:
MS
neoplasm
spinal cord injury
syringomyelia
stroke

FS: can use VINDICATE NP

Question 3

List clinical characteristics of neuropathic pain in terms of:
- onset from nerve injury
- persistence
- associate symptoms

Answer 3

1. May develop immediately after a nerve injury/disease or as late effect several months later
2. Likely to be chronic with spontaneous & evoked pain perceived as hyposensitivity or hypersensitivity
3. In some cases, can be acute/reversible
   (i.e. cold evoked pain after oxaliplatin)
4. Paraesthesia, dysaesthesia, allodynia, hyperalgesia may be present

Question 4

Define the difference between the following 4 terms:
Paraesthesia
Dysaesthesia
Allodynia (name 2 common types)
Hyperalgesia

Answer 4

1. Paraesthesia - spontaneous/evoked abnormal sensation that is not painful or unpleasant (numbness / tingling)
2. Dysaesthesia - spontaneous/evoked unpleasant abnormal sensation (pain)
3. Allodynia: type of evoked pain that is elicited by non-noxious stimulation. Most common types are:

i) touch-evoked (dynamic mechanical) allodynia
light touch causes pain (clothing)

ii) cold allodynia - contact with cold

4. Hyperalgesia: increased response to a stimulus that is normally painful
   (often present but not reported as a symptom by patient)

Question 5

List three requirements for a formal diagnosis of neuropathic pain

Answer 5

1. Demonstrate a nervous system lesion
2. Relevant onset of pain related to this lesion
3. Location of pain in areas of sensory disturbance that are neuroanatomically compatible with the lesion

**Diagnosis cannot rely on single pain descriptors

FS: source, onset, location

Question 6

List 3 challenges in diagnosing neuropathic pain

Answer 6

1. When neuropathic and nociceptive components of pain occur together (history)
2. When sensory loss is masked by areas of hypersensitivity (physical)
3. It’s not alway easy to confirm (investigations)

Question 7

1. List 1 important feature of neurological exam in diagnosing neuropathic pain
2. List 3 diagnostic tests that may aid in the diagnosis of neuropathic pain

Answer 7

1. Sensory exam including responses to touch, vibration, pinprick, thermal stimuli + mapping of sensory dysfunction
2. quantitative sensory testing
   CT/MRI*
   EMG*
   nerve conduction velocity testing
   nerve biopsy*

Question 8

List and describe 3 levels of a grading system that proposes certainty with which a pain is neuropathic.

Answer 8

Possible neuropathic pain:

• History of neurological lesion OR
• onset of sensory dysfunction
• in area neuroanatomically plausible with the lesion + onset consistent with the lesion

Probably neuropathic pain:

• Clinical exam demonstrates sensory loss in a neuroanatomically plausible area

Definite neuropathic pain:

• If an objective test (neurophysiological or imaging) confirms the neurological lesion

FS: basically diagnosis needs (!!!)
History - LOPQRST
Physical - especially sensory exam
Investigations

Question 9

What are 3 tools that can be used to identify neuropathic pain ?*

Answer 9

1. Algorithms used to identify neuropathic pain syndromes (**not shown in text, include from cited paper??)
2. Questionnaires based on symptoms such as:
   burning, painful cold, electric shocks, pin&needles, tingling, numbness, itching
   (OK to use in epidemiological research but NOT to confirm Dx - need clinical exam)
3. Clinical practice guidelines (i.e. to measure chemotherapy-induced neuropathy)

Question 10

What is the burden of neuropathic pain syndromes in cancer patients? (%)

Give 5 examples of neuropathic pain syndromes in this population

Answer 10

1. Estimated to affect up to 40% of cancer patients
   - 20% neuropathic pain
   - up to 40% when mixed pain included

• Mononeuropathy/plexopathy from tumour infiltration of periperhal nerves
• Tumours within brain + spinal cord or SCC
• Polyneuropathy from malnutrition or paraneoplastic syndromes
• Complication of surgery/radiotherapy
• Chemotherapy induced peripheral neuropathy

Neuropathic pain can persist in survivors independently of cancer.

FS:
Peripheral
1. Chemo CIPV
2. Surgery/radiation
3. Brachial plexus
4. Celiac plexus
5. Nerve root impingement

Central
1. SCC
2. Brain Mets
3. Leptomeningeal Mets

Question 11

1. List 4 classes of chemotherapy known to be neurotoxic/ cause CIPN

Answer 11

1. Platinum (cisplatin, carboplatin, oxaliplatin)
2. Taxanes (docetaxel, paclitaxel)
3. Vinca alkaloids ( vincristine, vinblastine)
4. Proteasome inhibitors
5. Myeloma treatment (thalidomide, lenalidomide, pomalidomide)

Fs: COP-MV

Question 12

List features of chemotherapy induced peripheral neuropathy
- relationship to dosage
- distribution
- associated symptoms
- presentation with different chemos

Answer 12

1. Usually dose-dependent , cumulative side effect
2. Glove and stocking distribution
3. Symptoms include sensory loss, paraesthesia, dysaesthesia, pain +/- cramps/weakness
4. Different clinical presentations with different chemos:

• Platinums: coasting phenom –> neuropathy worsens months after d/c therapy

-Oxaliplatin:
acute phase with cold allodynia
pricking dysaesthesia affecting hands/peri-oral area
pharyngolaryngeal dysaesthesia with SOB
swallowing issues with cold drinks/cold wind
may be independent of developing sensory PN

Question 13

What is the evidence for analgesics in treating cancer related neuropathic pain?

Answer 13

The quality of evidence on effectiveness of analgesics recommended as 1st line for neuropathic pain is LOW.

Extrapolate from studies in other neuropathic pain syndromes (e.g. belief is that neuropathic pain in CIPN is no different from PDN)

Question 14

What type of nerve fibres do EMG and nerve conduction studies assess?

Answer 14

large muscle fibre function

Question 15

How are anticonvulsants thought to have an analgesic effect in neuropathic pain?

Answer 15

They interfere with processes involved in neuronal hyperexcitability - either by:

1. decreasing excitatory transmission, or
2. increasing inhibitory transmission

therefore net neuronal depressant effect

Question 16

Name 3 chronic pain conditions in which the effects of gabapentin and pregabalin are well established. How effective are they (NNT)?

Answer 16

1. Post-herpetic neuralgia
2. Diabetic neuropathy
3. Spinal cord injury pain

Both are equally effective with average NNT = 7.5 for 50% pain reduction.

Question 17

How to gabapentin and pregabalin work?

Answer 17

Through antagonism of
alpha 2 delta subunit of
voltage dependent Ca2+ channels
at presynaptic sites

Ultimately decrease glutamate release

Question 18

List four side effects of gabapentinoids

Answer 18

Most common:
Somnolence*
Dizziness

Also:
Delirium*
asthenia
weight gain*
dry mouth*
peripheral edema*
nausea
vertigo
ataxia

Question 19

Other anticonvulsants for neuropathic pain:

1. How do carbamazepine and oxcarbamazepine work?
2. They are first line drugs for which condition?

Answer 19

1. sodium channel blocker
2. trigeminal neuralgia
   inconsistent evidence for other neuropathic pain syndromes

May help with pain from thermal or mechanical stimuli with preserved small fibre function (i.e. intact sensation to cold and warm)

Question 20

List two TCAs that are secondary amines.

List two TCAs that are tertiary amines. Which is better tolerated?

How should TCA’s be started and titrated?

What is 1 pharmacokinetic issue to anticipate?

Answer 20

desipramine, nortriptyline = secondary amines => better tolerated (also less sedating)

amitriptyline, clomipramine, and imipramine = tertiary amines
(imipramine also less sedating)

Tertiary amines not recommended at doses >75mg/day in age >65 due to side effects

Start at 25 mg daily (10 mg in elderly).
Increase by 25 mg q 3-7 days
up to 50-150 mg daily

Genetic polymorphism in TCA metabolizing enzymes. Patients may have supra or subtherapeutic concentrations at same dose.

Question 21

List four side effects of carbamazepine and oxcarbamazepine. Which is better tolerated?

Answer 21

Oxcarbamazepine is better tolerated

SE: nausea, dry mouth, weight gain, drowsiness, dizziness, confusion, ataxia, diplopia, rash, hyponatremia, blood dyscrasia (rare)

FS: SEs Same as Gaba

Question 22

List two contraindications for use of carbamazepine

Answer 22

AV block and hepatic insufficiency

Question 23

What is the evidence for non-gabapentinoid anti-convulsants in neuropathic pain?
- Lamotrigine
- Topiramate
- Valproate
- Levetiracetem

Answer 23

Inconclusive evidence for lamotrigine, lacosamide, and topiramate other than for trigeminal neuralgia

Valproate and levetiracetem - recommendations against their use for neuropathic pain

Question 24

List two classes of antidepressants well established for use in treatment of neuropathic pain

Answer 24

TCAs, SNRIs (selective seritonin noradrenaline reuptake inhibitors)

Question 25

What is the NNT for TCA's in neuropathic pain conditions?

Answer 25

In small RCTs, combined NNT = 3.6 but due to issues with studies, can't compare directly to NNT of gabapentinoids and duloxetine.

Question 26

List four side effects of TCAs

Answer 26

``` dry mouth nausea confusion constipation urinary retention sweating blurred vision somnolence confusion orthostatic hypotension gait disturbance cardiotoxicity ``` Contraindicated in pts with epilepsy, cardiac failure, conduction blocks FS: antichol toxidrome

Question 27

What is the NNT for SNRI's in neuropathic pain?

Answer 27

Randomized trials show effect of venlafaxine and duloxetine in PDN and CIPN Combined NNT was 6.4 Effect of duloxetine present at week 1 and most effective/less side effects at dose of 60 mg daily

Question 28

List four side effects of SNRIs

Answer 28

``` nausea (most common) somnolence dizziness constipation anorexia hyperhidrosis decreased libido erectile dysfunction ejaculation failure hypertension ``` FS: NASH

Question 29

In neuropathic pain, what are the considerations for starting, titrating, and contraindications i) duloxetine ii) venlafaxine

Answer 29

Duloxetine: Start at 30 mg daily Can increase to 60 mg after 1 week Do not use in hepatic dysfunction Venlafaxine Start at 37.5 mg daily Increase by 75 mg weekly up to 150-225 mg daily Should be decreased in hepatic/renal dysfunction

Question 30

What do recent treatment guidelines recommend re: cannabinoids for neuropathic pain? List three side effects of cannabinoids. Other than neuropathic pain, what two symptoms is there evidence of this class of medication helping with

Answer 30

Weak recommendation against the use of cannabinoids for neuropathic pain due to lack of effect (except for acute trials) and concerns about side effects ``` dizziness drowsiness impaired psychomotor function dry mouth dysphoria ``` nausea anorexia

Question 31

1. What neurotransmitter does capsaicin work on? 2. What is the role for capsaicin in neuropathic pain? Name a condition it treats 3. How is it applied? 4. List: 1 benefit and 1 downside

Answer 31

1. depletes substance P from primary afferent nociceptors 2. 2nd line treatment for peripheral NP. At least 12 week modest reduction in pain with application of single high conc. (8%) patch in painful PN, post herpetic neuralgia 3. HCP has to apply high conc (8%) patch x 30-60 min. Can apply up to 4 patches at once. Low conc patch (0.075%) apply x 1 week for regional nerve pain and joint pain 4. Benefit: treatment has long term effect no or limited systemic exposure/SE* Downside: effective size is small* application is painful (needs prior local anesthetic)

Question 32

1. What is the NNT for opioids in neuropathic pain? 2. Is there a diff effect between diff opioids? 3. When should opioids be used in neuropathic pain - name 3 situations

Answer 32

1. Tramadol NNT: 4.7 Strong opioids: 4.3 2. No proven difference between opioids 3. Lack of benefit from first line drug classes (ie tramadol 2nd line, strong opioids 3rd line) or Patients with episodic pain or Patients with coexisting cancer related non-neuropathic pain

Question 33

1. What is the role of Botulinim toxin type A in neuropathic pain? 2. What is the mechanism of action? 3. How is it administered? 4. Name 1 side effect

Answer 33

1. Considered 3rd line treatment for neuropathic pain 2. BTX is a neuroparalytic agent produced by the bacterium Clostridium botulinum: irreversibly inhibits acetylcholine release at the neuromuscular junction --> reduce muscle contraction and painful muscle spasm; may also block peripheral sensitization and indirectly reduce central sensitization 3. Injected intradermally in the painful area 4. Pain on application but otherwise no other known local or systemic side effects

Question 34

Name 2 NMDA antagonists (not methadone) What is their evidence in neuropathic pain?

Answer 34

Oral options such as dextromethorphan, memantine show low response rates + unfavourable therapeutic indices

Question 35

List four non-pharmacologic techniques that can be used for neuropathic pain

Answer 35

``` CBT * physiotherapy massage* acupuncture* fitness/exercise mind-body techniques* sympathetic blockade spinal cord/motor cortex stimulation* neurosurgery ```

Question 36

List the first line agent for neuropathic pain in the following conditions ``` trigeminal neuralgia other neuropathic conditions focal pain concurrent depression concurrent anxiety ```

Answer 36

``` trigeminal neuralgia - carbamazepine other neuropathic conditions - TCAs, gabapentinoids, SNRIs focal pain - topical lidocaine patch concurrent depression - SNRIs TCAs concurrent anxiety - pregabalin ```

Question 37

According to the Neuropathic Pain Special Interest group, what are the 1st to 3rd line medications for neuropathic pain?

Answer 37

1st line TCA's, SNRI's, gabapentinoids 2nd line: TP Tramadol Patches x 2 types - lidocaine and capsaicin 3rd line: Opioids (strong) botulinim toxin type A

Question 38

Lidocaine patch is considered 2nd line treatment for peripheral neuropathic pain. - How is this administered? - Name 1 benefit, 1 side effect, 1 contraindication of the drug

Answer 38

Up to 3-4 patches can be applied to intact skin for 12 hours/day Benefit: - lack of systemic side effects (positive for elderly and can also use as add on therapy due to lack of drug-drug interaction) Side effect: mild skin irritation Contraindication: Although minimal absorption, do not use in patients taking class I antiarrhythmic drugs

Question 39

List 3 pros and 2 cons of combination therapy for neuropathic pain

Answer 39

PROS: 1. May allow for reduction of opioid dose (in patients on opioid for nociceptive pain) 2. May improve pain if single drug only partly effective 3. Some combos may reduce side effects CONS: 1. Risk of additional side effects/polypharmacy 2. Risk of medication overuse 3. Risk of noncompliance 4. Despite clinical practice, overall lack of information on combo therapy

Question 40

List 5 general principles for the approach of neuropathic pain management

Answer 40

1. First step is to thoroughly assess and diagnose neuropathic pain syndrome + underlying mechanism 2. Whenever possible, treat underlying disease 3. Whether or not #2 can happen, treatment of pain/disability should be offered. 4. Set realistic expectations- often only partial pain relief from neuropathic pain can be expected 5. Giving patient info about pain is important/therapeutic. FS: 1. Assess 2. Treat underlying condition 3. Treat symptom 4. Set expectations 5. Educate