NEUROPATHIC PAIN AND

DIFFICULT PAIN
Dr Anuja Damani
Associate Professor
Department of Palliative Medicine and Supportive Care
Kasturba Medical College, MAHE, Manipal
1/27/2024
 KEY MESSAGE

Bone, abdominal and neuropathic pain

are frequently devastating and require
a complex interdisciplinary approach
to management

1/27/2024
 OBJECTIVES
• Pathophysiology
• Management strategies

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 BONE PAIN...

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 VISHWAS, 73 YO,
• Ca Prostate
• Pain today
• Increased pain while
sitting and walking
• Shooting pain
perineum
• Cold legs
• Numbness
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 PATHOPHYSIOLOGY
• Direct stimulation of nociceptors
• Pressure from expanding mass in
closed space
• Prostaglandin synthesis
Chemical stimulation of nociceptors
Inflammation ➔ edema ➔ pressure
• Nerve infiltration / destruction
• Neuropathic pain
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 RADIOGRAPHIC ASSESSMENT
• Cortical thinning
• Lytic metastases
• Consider
Risk of fracture
Pin before fracture

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 MANAGEMENT
• Opioids
• Acetaminophen
• NSAIDs
• Dexamethasone
• Bisphosphonates
• Radiation
• Immobilization
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 ABDOMINAL PAIN...

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 PATHOPHYSIOLOGY
• Nociceptive
Peritoneum – stretch
Masses, inflammation
Body wall – chemical, pressure, temperature
• Neuropathic
Compression
Infiltration / destruction

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 JAGDISH, 54 YO
• Cancer liver x 1 year
• 3 months  abdominal distention
• Bloating, distention
• Diffuse, abdominal discomfort CAUSE?
• 5 / 10 when sitting or standing
• 6 – 7 / 10 when lying down
• Intermittent heartburn
• Trouble catching breath

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 ASCITES
• Diuretics
• Spironolactone
• Na+ restriction
• Paracentesis

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 JAGDISH… FEW WEEKS LATER

•“ More intense ” pain R upper abdomen x 1

week
•Worse with movement, deep breaths
•Intermittent, sharp pain in R shoulder
Cause ?
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 HEPATOMEGALY WITH
DIAPHRAGMATIC IRRITATION
•Steroids, e.g., Dexamethasone
• Start high dose 8+ mg once daily
• t ½ ≈ 36 hrs
• Titrate to lowest effective dose
• Risk of late effects at 3+ months
• Cushingoid features
• Proximal muscle wasting
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 VAISHALI, 49 YO
• Fatigue, anorexia
• 5 kg weight  in 3 months
• 1st, abdo discomfort, worse with eating
• Later, “gnawing ache” lower thoracic region in midline
radiating ➔ back
•  lying down;  sitting up
• Developed jaundice
• CT scan = mass head of pancreas +
CAUSE?
multiple small liver masses
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 PANCREATIC INVASION

•Celiac plexus block early

• Effect lasts 3+ months
• Can repeat
•Opioids
•Steroids

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 KAMALA, 35 YO
• Metastatic ovarian cancer
• Distension, belching, anorexia
• No bowel movement x 2 weeks
• No flatus
• Diffuse lower abdominal pain / pressure
• Severe intermittent nausea / vomiting
Cause ?
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 BOWEL DISTENTION
DUE TO OBSTRUCTION…
•Traditionally
• Nasogastric suction + IV fluids
• Dexamethasone – decrease inflammation
• Metoclopramide – relieve obstruction
• Surgical decompression
• Ostomy, G or J-tube drainage

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 …BOWEL DISTENTION
DUE TO OBSTRUCTION
• More effective to  fluids into gut
• Somatostatin ( Octreotide )
• Inhibits active pumps  secretions
• Infusion 10 – 80+ mcg / hr as t½ = 1.5 hr
• Scopolamine ( Hyoscine )
• Anticholinergic effect  secretions
• Bolus 0.1 – 0.4 mg q8h as as t½ = 8 hr
• Infusion 0.1 – 1.2+ mg / hr
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NEUROPATHIC PAIN...

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IASP 2008
Pain

Neuropathic Pain: Pain arising as a direct

consequence of a
lesion or disease affecting the somatosensory
system
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 CAUSES
• Chemotherapy
• Compression – disc, metastases
• Infection – HIV, herpes
• Infiltration – cancer
• Ischemia – compromised arterial or
venous circulation, edema, pressure
• Metabolic injury – diabetes
• Transection – amputation

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 Somatic or Visceral
NOCICEPTIVE Pain NEUROPATHIC

ACUTE PROLONGED CHRONIC

PROTECTIVE NON-PROTECTIVE
PERIPHERAL CENTRAL

REFLEXES INFLAMMATION SYMPATHETIC

1/27/2024 AND REPAIR
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 PATHOPHYSIOLOGY –
MULTIPLE CONCURRENT MECHANISMS

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Gilron I et al. CMAJ 2006; 175(3): 265-273
PERIPHERAL MECHANISMS…

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PERIPHERAL TRANSDUCTION DYSFUNCTION
• Membrane excitability
• Demyelination
( ephaptic transmission )
• Regeneration
➔ neuromas
➔ new projections into uninjured areas
➔ expanded receptive fields
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 PERIPHERAL SENSITIZATION -
PRIMARY AFFERENTS
•  expression of Na+
channels

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 SYNAPTIC TRANSMISSION DYSFUNCTION
• Voltage-gated
Ca2+ channels
↑ stimulation
→ Change charge
→ Ca2+ entry
→ releases
Substance P
Glutamate
Other neurotransmitters
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CENTRAL MECHANISMS…

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 CENTRAL SENSITIZATION
• NMDA (N-methyl-D-aspartate)
receptor mediated (dorsal horn)

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 NMDA-GLUTAMATE RECEPTORS
• Normally blocked by Mg2+, inactive
•  glutamate & glycine
➔ Change charge
➔ Mg2+ released
➔ channel opens
➔  opioid
responsiveness
➔ allodynia
➔ hyperalgesia
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 CENTRAL SENSITIZATION

10 Hyperalgesia

8 Normal
Pain
Pain Intensity

Response
6 Injury
Allodynia Hyperalgesia – Increased
4 pain sensitivity
Allodynia – Pain in
response to a
2
non-nociceptive stimulus

Stimulus Intensity
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Gottschalk A, Smith DS. Am Fam Physician. 2001;1979-84.
 REDUCED INHIBITION
• Descending pathways
• Noradrenaline
• Serotonin

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 GLIAL CELL ACTIVATION
• Release pro-nociceptive
cytokines
• Interleukin-1
• Tumor necrosis
factor
• Neurotrophins
➔  nociceptive
transmission
➔  sensitization
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 SYMPATHETICALLY MAINTAINED
• Sprouting of sympathetic neurons in
• Dorsal root ganglia
• Dermis

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 PATIENT EXPERIENCE
( SOME – ALL – NONE )
• Described as • Associated
• Burning • Numbness, tingling
• Shooting • Weakness, clumsiness
• Electrical • Loss of reflexes
• Freezing • Autonomic dysfunction
• Aching • Swelling, sweating,
• Stocking-glove skin changes
• Radiation
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MANAGEMENT…

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 EVIDENCE…
• Therapies extrapolated from
non-cancer pain
• Diabetic peripheral neuropathy ( DPN )
• Post-herpetic neuralgia ( PHN )
• Few RCTs
• Very few comparative trials
• Trial and error
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 GUIDED BY…
• Diagnosis
• Treat underlying cause
• Assessment / neurological localization
• Inferred mechanisms
• Efficacy
• Safety / tolerability
• Ease of use
• Cost
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 JANARDHAN, 62 YO
• Cough, weight loss
• Non small cell Ca R upper lung
• Cisplatin-based chemotherapy
• Developed peripheral neuropathy
• Stocking – glove
• 4 / 10
• Hyperalgesia
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 CHEMOTHERAPY-INDUCED
PERIPHERAL NEUROPATHY
Affect neuronal cell body, axonal transport system,
myelin sheath, glial support structures
• Pure Sensory • Mixed Sensorimotor
• Platins + / - autonomic
• Cisplatin • Taxanes
• Oxaliplatin • Paclitaxel
• Carboplatin • Docetaxel
• Vinca-alkaloids
Quasthoff S, Hartung HP. J Neurology. 2002; 249(1): 9-17.
Malik B, Stillman M. Curr Neurol Neurosci Rep. 2008 Jan; 8(1):
• Vincristine
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56-65.
 GABAPENTINOIDS…
• Act on voltage-gated Ca2+ channel, modulating alpha-2-
delta protein
• Positive RCT’s
• Gabapentin: PHN, DPN, neuropathic cancer pain
• Pregabalin: PHN, DPN, fibromyalgia
• NNT less favorable than TCAs
• First-line 2º safety
• Not hepatically metabolized
• No drug interactions
• Side effects usually tolerable
Backonja et al, JAMA. 1998;280:1831-1836. Rowbotham M, JAMA.1998;280:1837-1842.
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Caraceni et al, J Clin Oncol, 2004;22:2909-2914.
 …GABAPENTINOIDS
• Pregabalin vs. gabapentin
• Easier to titrate
• Faster onset
• ↑ sleep, ↓ anxiety
• Cost pregabalin >> gabapentin
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• Trial gabapentin
• Start 100 – 300 mg qhs
• Daily, increase 100 mg q8h
• Effective 900 – 1800 mg / 24 hr
• Max 3600 – 5400 mg / 24 hr
• If ineffective, pregabalin
• Start 25 – 75 mg q12h
• Increase 25 mg q12h
• Effective 100 – 150 mg / 24 hr
• Max 300 – 600 mg / 24 hr
 ANTIDEPRESSANTS AS ANALGESICS
• Efficacy Noradrenaline ( N )
& Serotonin ( S )
• TCAs, amitriptyline
(N & S RI)

• ≈ desipramine, nortriptyline
(N RI)
• > Mixed SNRIs, duloxetine,
venlafaxine
• > SSRIs, citalopram, paroxetine
Dworkin RH, et al, Arch Neurol. 2003;60:1524-1534.
1/27/2024
Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Pain. 2005;118(3):289-305.
 ANTIDEPRESSANTS AS ANALGESICS
Efficacy Noradrenaline ( N ) Side effects
& Serotonin ( S )
TCAs, amitriptyline ( N & S RI ) Greatest = CNS,
anticholinergic, nausea, CV

≈ desipramine, nortriptyline (N
> Less
RI)
> Mixed SNRIs, duloxetine,
> Least = sexual
venlafaxine
≈ Least = sexual
> SSRIs, citalopram, paroxetine
Dworkin RH, et al, Arch Neurol. 2003;60:1524-1534.
1/27/2024
Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Pain. 2005;118(3):289-305.
 …ANTIDEPRESSANTS
• Desipramine 10 – 25 mg PO qhs
• Increase by 10 – 25 mg qhs every 3 – 5 days ( t ½ up to 24
hrs )
• If dose > 100 mg qhs could be effect, assess blood
levels for risk of toxicity

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 ANTICONVULSANTS
•  excitation (  Na + / K+ flux )
• Limited data, trial-and-error
• Newer drugs have better safety profiles
Lamotrigine Carbamazepine ( PHN )
Topiramate Phenytoin
Oxcarbazepine Valproate
Tiagabine
Levetiracetam
Zonisamide
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 ANTICONVULSANTS
• Carbamazepine 50 – 100 mg q12h
• Increase by 50 – 100 mg every 3 days
• t ½ = 12 hrs
• Monitor blood levels for risk of toxicity

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 JANARDHAN, 62 YO, NSCCL
• 3 months later, 2 wk Hx
• Forearm – intermittent stabbing pain
• Elbow – severe aching
• Hand –  burning
• 8 / 10 with optimal gabapentin
• Increased apical mass ➔ plexopathy
• Mixed nociceptive & neuropathic pain

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 OPIOIDS, POSITIVE TRIALS
Morphine PHN
Oxycodone DPN & PHN
Methadone Mixed neuropathic pain
Levorphanol Peripheral & central neuropathic pain
Morphine + gabapentin vs. morphine alone vs. gabapentin
DPN or PHN
Systematic review of tramadol ( 5 trials )
Gimbel JS et al: Neurology 2003;60:927-934. Watson CP, Babul N: Neurology 998;50:1837-1841. Morley JS et al: Palliat Med
2003;7:576-587.
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Raja SN et al: Neurology 2002;59:1015-1021. Rowbotham MC, et al: NEJM 2003;348:1223-1232. Duhmke RM, et
al. Cochrane Database Syst Rev 2004:CD003726. Gilron I, et al: NEJM 2005;352:1324-1334.
 OPIOIDS
• Nociceptive pain > neuropathic pain
• First-line for moderate to severe
neuropathic pain
• Titrate to effect or intolerable side-effects
• Poor response, more likely neuropathic pain

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 METHADONE
• Racemic mixture
• Mu-agonist opioid +
• NMDA receptor antagonist
• Single opioid
• Titrate to effect or intolerable side-effects
• Long half-life; NOT first order kinetics
• Experienced palliative care, pain experts
• Coanalgesic 2.5 – 5+ mg q8h
• Cost PO << parenteral
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Fast Facts, see www.eperc.mcw.edu/ff_index.htm
 CORTICOSTEROIDS
• Limited data, widely used in
• Bone pain
• Neuropathic pain
• Lymphedema
• Other conditions
• Dexamethasone
• Start high dose 8+ mg once daily
• Titrate to lowest effective dose
• Risk of late effects at 3+ months
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 JANARDHAN, 62 YO, NSCCL
• 1 week later
• Burning, stabbing pain not controlled
• 7 / 10
• Allodynia
• Gabapentin, morphine + methadone, dexamethasone

• Consult palliative care or pain experts

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 SODIUM CHANNEL BLOCKERS -
IV LIDOCAINE
• RCTs for severe neuropathic
pain
• Loading dose
• 2 mg / kg IV over 15 – 20
min, reassess pain 30 min
post infusion
• If pain improved
• Continuous infusion
1 – 3 mg / kg / hr
Oskarsson P et al, Diabetes Care, 1997;20:1594-1597.
1/27/2024
Challapalli et al, Cochrane Database Sys Rev. 2005;CD003345.
 SODIUM CHANNEL BLOCKERS -
IV LIDOCAINE
• RCTs for severe neuropathic • Lidocaine level
pain 8 – 10 hours after start of
• Loading dose infusion
• 2 mg / kg IV over 15 – 20 • Therapeutic level for
min, reassess pain 30 min analgesia is
post infusion 2 – 6 mcg / ml
• If pain improved • Monitor for side-effects
• Continuous infusion
1 – 3 mg / kg / hr
Oskarsson P et al, Diabetes Care, 1997;20:1594-1597.
1/27/2024
Challapalli et al, Cochrane Database Sys Rev. 2005;CD003345.
 NMDA RECEPTOR ANTAGONIST –
KETAMINE…
• Ketamine blocks PCP site in receptor channel
• RCTs
ketamine + opioids
by single bolus or infusion
• Mixed, generally positive results
• Water & lipid soluble
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 NMDA RECEPTOR ANTAGONIST –
…KETAMINE…
• PO ( eg, mucositis )
• Start 10 – 25 mg q8h
• Increase up to 0.5 – 1 mg / kg q8h
• Maximum 200 mg q6h
• SC bolus dosing ( eg, wound care )
• Use 10 – 25 mg ( 0.2 – 0.5 mg / kg )

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 NMDA RECEPTOR ANTAGONIST –
…KETAMINE
SC infusion
Start 0.1 – 0.2 mg / kg / hr
Titrate to pain relief or intolerable side-effects
Max 3.6 gm / 24 hr
Monitor pain, vital signs
Patients may experience dream-like feelings
Small doses of
Anti-sialagogue for excessive secretions
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Benzodiazepine for dysphoric feelings
 OTHER THERAPIES
• Pharmacological • Interventional Anesthesia
• Topical • Non-pharmacological
• Capsaicin • Acupuncture
• Lidocaine • Biofeedback
• Ketamine • TENS
• Cannabinoids • Counselling
• Integrative therapies
• Baclofen
• a-2 Adrenergic Agonists
• Clonidine
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 SMITA, 43 YO

• Metastatic colorectal cancer

• Sacral plexus destruction
• Complex pharmacology ineffective !
• Pain 6 / 10
• Side-effects
• Drowsiness
• Confusion
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 MULTIPLE ISSUES ➔ “ TOTAL PAIN ”

Disease
Physical Psychological
management

Loss, grief Social

End of life /
death Practical Spiritual
management
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 SMITA, 43 YO, CA COLON
• Acknowledge distress and
extend support
• Simplify medications
• Address multiple
psychosocial
spiritual issues
causing suffering
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 KEY MESSAGE

Bone, abdominal and neuropathic pain

are frequently devastating and require
a complex interdisciplinary approach
to management

1/27/2024
 THANK YOU

Questions?
anuja.damani@gmail.com

1/27/2024