7.15 (13.3) Management issues in neuropathic pain Flashcards
Define neuropathic pain
Heterogenous group of chronic pain conditions arising from a lesion or disease of the peripheral or central somatosensory nervous system
List four etiologies of peripheral neuropathic pain.
List four etiologies of central neuropathic pain
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
List clinical characteristics of neuropathic pain in terms of:
- onset from nerve injury
- persistence
- associate symptoms
- May develop immediately after a nerve injury/disease or as late effect several months later
- Likely to be chronic with spontaneous & evoked pain perceived as hyposensitivity or hypersensitivity
- In some cases, can be acute/reversible
(i.e. cold evoked pain after oxaliplatin) - Paraesthesia, dysaesthesia, allodynia, hyperalgesia may be present
Define the difference between the following 4 terms:
Paraesthesia
Dysaesthesia
Allodynia (name 2 common types)
Hyperalgesia
- Paraesthesia - spontaneous/evoked abnormal sensation that is not painful or unpleasant (numbness / tingling)
- Dysaesthesia - spontaneous/evoked unpleasant abnormal sensation (pain)
- 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
- Hyperalgesia: increased response to a stimulus that is normally painful
(often present but not reported as a symptom by patient)
List three requirements for a formal diagnosis of neuropathic pain
- Demonstrate a nervous system lesion
- Relevant onset of pain related to this lesion
- 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
List 3 challenges in diagnosing neuropathic pain
- When neuropathic and nociceptive components of pain occur together (history)
- When sensory loss is masked by areas of hypersensitivity (physical)
- It’s not alway easy to confirm (investigations)
- List 1 important feature of neurological exam in diagnosing neuropathic pain
- List 3 diagnostic tests that may aid in the diagnosis of neuropathic pain
- Sensory exam including responses to touch, vibration, pinprick, thermal stimuli + mapping of sensory dysfunction
- quantitative sensory testing
CT/MRI*
EMG*
nerve conduction velocity testing
nerve biopsy*
List and describe 3 levels of a grading system that proposes certainty with which a pain is neuropathic.
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
What are 3 tools that can be used to identify neuropathic pain ?*
- Algorithms used to identify neuropathic pain syndromes (**not shown in text, include from cited paper??)
- 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) - Clinical practice guidelines (i.e. to measure chemotherapy-induced neuropathy)
What is the burden of neuropathic pain syndromes in cancer patients? (%)
Give 5 examples of neuropathic pain syndromes in this population
- 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
- List 4 classes of chemotherapy known to be neurotoxic/ cause CIPN
- Platinum (cisplatin, carboplatin, oxaliplatin)
- Taxanes (docetaxel, paclitaxel)
- Vinca alkaloids ( vincristine, vinblastine)
- Proteasome inhibitors
- Myeloma treatment (thalidomide, lenalidomide, pomalidomide)
Fs: COP-MV
List features of chemotherapy induced peripheral neuropathy
- relationship to dosage
- distribution
- associated symptoms
- presentation with different chemos
- Usually dose-dependent , cumulative side effect
- Glove and stocking distribution
- Symptoms include sensory loss, paraesthesia, dysaesthesia, pain +/- cramps/weakness
- 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
What is the evidence for analgesics in treating cancer related neuropathic pain?
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)
What type of nerve fibres do EMG and nerve conduction studies assess?
large muscle fibre function
How are anticonvulsants thought to have an analgesic effect in neuropathic pain?
They interfere with processes involved in neuronal hyperexcitability - either by:
- decreasing excitatory transmission, or
- increasing inhibitory transmission
therefore net neuronal depressant effect
Name 3 chronic pain conditions in which the effects of gabapentin and pregabalin are well established. How effective are they (NNT)?
- Post-herpetic neuralgia
- Diabetic neuropathy
- Spinal cord injury pain
Both are equally effective with average NNT = 7.5 for 50% pain reduction.
How to gabapentin and pregabalin work?
Through antagonism of
alpha 2 delta subunit of
voltage dependent Ca2+ channels
at presynaptic sites
Ultimately decrease glutamate release
List four side effects of gabapentinoids
Most common:
Somnolence*
Dizziness
Also:
Delirium*
asthenia
weight gain*
dry mouth*
peripheral edema*
nausea
vertigo
ataxia
Other anticonvulsants for neuropathic pain:
- How do carbamazepine and oxcarbamazepine work?
- They are first line drugs for which condition?
- sodium channel blocker
- 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)
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?
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.
List four side effects of carbamazepine and oxcarbamazepine. Which is better tolerated?
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
List two contraindications for use of carbamazepine
AV block and hepatic insufficiency
What is the evidence for non-gabapentinoid anti-convulsants in neuropathic pain?
- Lamotrigine
- Topiramate
- Valproate
- Levetiracetem
Inconclusive evidence for lamotrigine, lacosamide, and topiramate other than for trigeminal neuralgia
Valproate and levetiracetem - recommendations against their use for neuropathic pain
List two classes of antidepressants well established for use in treatment of neuropathic pain
TCAs, SNRIs (selective seritonin noradrenaline reuptake inhibitors)
What is the NNT for TCA’s in neuropathic pain conditions?
In small RCTs, combined NNT = 3.6 but due to issues with studies, can’t compare directly to NNT of gabapentinoids and duloxetine.
List four side effects of TCAs
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
What is the NNT for SNRI’s in neuropathic pain?
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
List four side effects of SNRIs
nausea (most common) somnolence dizziness constipation anorexia hyperhidrosis decreased libido erectile dysfunction ejaculation failure hypertension
FS: NASH
In neuropathic pain, what are the considerations for starting, titrating, and contraindications
i) duloxetine
ii) venlafaxine
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
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
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
- What neurotransmitter does capsaicin work on?
- What is the role for capsaicin in neuropathic pain? Name a condition it treats
- How is it applied?
- List: 1 benefit and 1 downside
- depletes substance P from primary afferent nociceptors
- 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
- 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
Benefit:
treatment has long term effect
no or limited systemic exposure/SE*
Downside:
effective size is small*
application is painful (needs prior local anesthetic)
- What is the NNT for opioids in neuropathic pain?
- Is there a diff effect between diff opioids?
- When should opioids be used in neuropathic pain - name 3 situations
- Tramadol NNT: 4.7
Strong opioids: 4.3 - No proven difference between opioids
- 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
- What is the role of Botulinim toxin type A in neuropathic pain?
- What is the mechanism of action?
- How is it administered?
- Name 1 side effect
- Considered 3rd line treatment for neuropathic pain
- 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
- Injected intradermally in the painful area
- Pain on application but otherwise no other known local or systemic side effects
Name 2 NMDA antagonists (not methadone)
What is their evidence in neuropathic pain?
Oral options such as dextromethorphan, memantine show low response rates + unfavourable therapeutic indices
List four non-pharmacologic techniques that can be used for neuropathic pain
CBT * physiotherapy massage* acupuncture* fitness/exercise mind-body techniques* sympathetic blockade spinal cord/motor cortex stimulation* neurosurgery
List the first line agent for neuropathic pain in the following conditions
trigeminal neuralgia other neuropathic conditions focal pain concurrent depression concurrent anxiety
trigeminal neuralgia - carbamazepine other neuropathic conditions - TCAs, gabapentinoids, SNRIs focal pain - topical lidocaine patch concurrent depression - SNRIs TCAs concurrent anxiety - pregabalin
According to the Neuropathic Pain Special Interest group, what are the 1st to 3rd line medications for neuropathic pain?
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
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
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
List 3 pros and 2 cons of combination therapy for neuropathic pain
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
List 5 general principles for the approach of neuropathic pain management
- First step is to thoroughly assess and diagnose neuropathic pain syndrome + underlying mechanism
- Whenever possible, treat underlying disease
- Whether or not #2 can happen, treatment of pain/disability should be offered.
- Set realistic expectations- often only partial pain relief from neuropathic pain can be expected
- Giving patient info about pain is important/therapeutic.
FS:
1. Assess
2. Treat underlying condition
3. Treat symptom
4. Set expectations
5. Educate
