202406221859

Status:

Tags: Oncology, pain

Cancer pain

Risk factor:

smoking
insomnia
malignancy type:
- leukaemia
- lymphoma
- lung
- breast
- colorectal
Age <65

Cause of pain in cancer patients:

local mass effect
cancer-induced bone pain
- neuropathic + inflammatory pain
- either 1° bone malignancy or 2° bone met
- normal bone homeostasis disrupted ∵ ↑ osteoclast activity from ↑RANK ligand
- formation of abnormal periosteal microneuroma
  - stimulated by nerve growth factor
  - → further sensitised by inflammatory mediators
paraneoplastic effects
central sensitisation
- nociceptors sensitised by various inflammatory mediators e.g.
  - ATP
  - cytokines
  - endothelin
  - neurotrophic factors
- ↑ excitability at transcriptional or post-translational level
- ↓ firing threshold

Surgical

CPSP

chemotherapy

ADR from chemo → psychological morbidity → worsen pain state

Chemotherapy induced peripheral neuropathy (CIPN)

multifactorial
- mitochondrial toxicity
- proteosome inhibition
- anti-angiogenesis
- microtubule disruption
length dependent sensory neuropathy
- typically glove & stocking distribution
- some fine motor & balance effects ∵ abnormal proprioception
both loss of function + gain of function symptoms
risk factors
- pre-existing neuropathy
- smoking
- renal failure
- DM
chemo agents
- vincristine
- platinum compounds
- taxanes
  - paclitaxel
  - docetaxel

RT

tissue damage from
- direct cell injury from ionising radiation
- inflammation
- oxidative stress
- triggering innate immune response
alter gene expression → release proinflammatory cytokines
proinflammatory state → fibrosis
- acute radiation fibrosis syndrome
  - w/i days to wks of treatment
- chronic radiation fibrosis syndrome
  - months to years after treatment
radiation induced peripheral neuropathy
- progressive & irreversible
- can present years after treatment cessation
- ∵ direct axonal injury, demyelination, injury to vasculature → ischaemia
  - together w/ fibrosis → chronic peripheral neuropathy

Examples of radiotherapy-induced pain syndromes and associated symptoms.

Acute phase radiation-related pain	Symptoms	Late phase radiation-related pain	Symptoms
Enteritis	Abdominal pain Diarrhoea Vomiting	Radiation fibrosis syndrome	Dependent on area affected - dystonia - muscle spasm - lymphoedema
Oesophagitis	Dysphagia Vomiting Reflux Cough	Osteoradionecrosis of jaw	Pain Trismus Orocutaneous fistula Non-healing ulcers
Oral mucositis	Oral Pain Ulcers Dysgeusia Weight loss (secondary decreased oral intake)	Oesophageal stricture	Reflux Bitter/acid taste Hiccups Dysphagia Weight loss
Proctitis	Tenesmus Pus/blood in stool Diarrhoea Abdominal pain	Dyspareunia	Painful intercourse
Dermatitis	Colour changes Swelling Desquamation/skin breakdown	Lower GI tract stricture	Painful defaecation (anal stricture) Bowel obstruction
		Peripheral neuropathy	Gain or loss of function neuropathic symptoms

Adjunctive therapy

Aromatase inhibitors

treat & prevent recurrence of oestrogen receptor-positive breast cancer
inhibit aromatase which converts androgens into oestrogens
Aromatase inhibitor-associated arthralgia

polyarthralgia
affecting mainly the wrists, hands and knees
affects around 50% of those taking AIs
may have an impact on treatment compliance in 20% of those affected
potential aetiology
- oestrogen depletion
- cytokine release
- Vitamin D deficiency

Immunotherapy

can cause a wide range of pain symptoms
- abdominal pain
- arthralgia and myalgia
- arthritis
- colitis
- pancreatitis
- dermatological blisters/sores
- neuropathic pain
Immune checkpoint inhibitors → rheumatological adverse reactions
- up to 10% of patients
- arthralgia
- inflammatory myositis
- systemic lupus erythematosus (SLE)/Sicca syndrome
- sarcoidosis
- vasculitis with associated neuropathy
- intensity can be severe, requiring the of cessation of treatment and initiation of immunosuppression

Associated conditions

hypercalcaemia
- PTH-RP
osteoporotic fracture
prolonged immobility + deconditioning + malnutrition
- pressure sore
immunosuppression
- skin abscess
- herpes zoster

unrelated conditions

↑ Mental health condition
MSK
chronic primary pain
headache

Management

Non-pharmacological adjuncts:

massage
physiotherapy
hypnotherapy
music therapy
Prehabilitation is the process of optimising physical and psychological health before an invasive treatment such as major surgery. It has been demonstrated to decrease postoperative pain and increase functional levels.

Pharmacological

ESMO (European Society for Medical Oncology) clinical practice guidelines:

Condition	Recommendation	Level of recommendation
Mild pain	WHO ladder Paracetamol—no evidence to support or refute NSAID—no evidence to support or refute	II, B I, C I, C
Moderate pain	Weak opioids in combination with non-opioids Low-dose strong opioids is alternative	III, C II, C
Severe pain	Oral morphine first line Fentanyl/buprenorphine safest in eGFR <30 Subcutaneous route considered if failed p.o. or TD I.V. infusion only considered when s.c. contraindicated For rapid pain control use i.v. opioid	I, A III, B III, B III, B III, B
Breakthrough pain	Immediate-release opioids	I, A
Bone pain	External beam radiotherapy (8 Gy single dose) Denosumab	I, A III, A
Neuropathic pain	First line: gabapentinoid, tricyclic antidepressant or duloxetine Interventional treatments have inconclusive evidence	I, A II, C
Interventions	Cordotomy should be available in refractory cases Coeliac plexus block indicated in pancreatic cancer	V, C II, B

WHO pain ladder

Since 1986
most effective at acute nociceptive cancer pain.
- may not represent the optimal approach in all patients
  - ∵ changing nature of cancer pain from acute → chronic
based around opioid escalation
- both strength & dose
not written specifically for neuropathic pain
- Antineuropathic agents recommended in the updated WHO guidelines
  - but as adjunctive therapies
  - limited guidance on how or when they should be used
- not include gabapentinoid & SNRI
  - both have a role in treatment of neuropathic pain
→ starting point for non-specialist

Topical agents

most commonly used for CIPN
Menthol cream
- acts on the transient receptor potential melastatin 8 (TRPM8)
  - upregulated in neuropathic pain
LA topically either via patches or cream (EMLA/AMETOP)
- RCT evidence supporting use is limited
- shown to be effective in individual studies
Capsaicin
- agonist of TRPV1
- depletes neuronal substance P
  - → desensitises TRPV1 receptors → analgesia
Doxepin
- TCA

Opioid

particularly effective for acute nociceptive pain
less appropriate for chronic pain
- ∵ ADR
  - potential for addiction
  - opioid induced hyperalgesia
worsening cancer survival outcomes
- limited evidence & controversial
- ? ∵ immunological & proangiogenic properties of opioids
- interaction w/ TLR4 receptors
- → can be used safely when monitored appropriately
concerns around opioids weighed against potential pro-oncogenic properties of pain itself
- ∵ adrenergic effects on cancer cells

NSAID

Non-steroidal anti-inflammatory drugs are effective non-opioid drugs for a variety of acute and chronic pain syndromes

Antineuropathic agents

WHO: no recommendation for or against ANY agents
Cochrane review: duloxetine supported by most robust evidence

IASP NeupSIG recommendations for the management of neuropathic pain in adults.

Recommended	Inconclusive evidence	Weak against	Strong against
TCA SNRIs Pregabalin Gabapentin Lidocaine patch Capsaicin patch Tramadol Botulin toxin A	Capsaicin cream Carbamazepine Topical clonidine Lamotrigine NMDA antagonists Oxycarbazepine SSRI antidepressants Tapentadol Topiramate Zonisamide	Cannabinoids Sodium valproate	Levetiracetam Mexiletine
ESMO cancer pain guidelines regarding medication for neuropathic cancer pain.

Recommended	No recommendation for or against	Recommended against
TCA		Ketamine
Gabapentin		Levetiracetam
Pregabalin		Mexiletine
Duloxetine
Opioids

Cannabinoids

animal model studies demonstrating benefit of cannabinoids in CIPN
inconclusive benefit from recent meta-analysis
∵ immunomodulatory effects of cannabinoids
- → some evidence of negative survival outcomes in patients receiving immunotherapy

Botox

increasingly used in chronic pain
dual mechanism of action
- At NMJ prevent the release of acetylcholine
  - useful in pain of MSK origin
- action on sensory nerves
  - inhibits the release of neurotransmitters & inflammatory agents
    - ∴ useful in localised neuropathic pain

Intervention: neuromodulation

Neuromodulation is the process by which nerve function can be altered by the direct application of electricity or biochemicals to neurones

Acupuncture

mediating the release of opioid peptides, serotonin & other local & systemic signalling molecules
acupuncture plus drug therapy more effective than conventional drug therapy alone for cancer-related pain
its use in an integrated fashion in cancer pain is recommended by the American Society of Clinical Oncology

Transcutaneous electrical nerve stimulation (TENS)

noninvasive neuromodulation technique
placing small skin electrodes over peripheral nerves or the spinal cord
evidence controversial
favourable risk–benefit profile & low cost
- → should be considered as part of multimodal analgesic strategy.

Peripheral nerve stimulation

if pain limited to discrete locations or dermatomes specific nerves
- can be targeted using stimulators implanted percutaneously
may be used in CIPN

Spinal cord stimulation

Pain signals modulated centrally
- deep brain stimulation (DBS)
- spinal cord stimulation (SCS)
placing electrodes into the epidural space either percutaneously or surgically
gate control theory of pain
- stimulation of A-β fibres prevents transmission of nociceptive input from A-δ and C fibres

Intrathecal drug delivery

Principle
- Systemic opioids deliver most of therapeutic effect via central μ opioid receptors
- ADR predominantly mediated by peripheral receptors
  - little or no benefit of analgesia
↓↓ doses of drug can be introduced directly to the site of action
- oral : intrathecal = 300 : 1
- ↑↑ analgesia whilst ↓↓ adverse effects
single shot (e.g. as adjunct to acute pain from surgery) vs intrathecal catheter
externalised vs implanted pump for longer term use
For drug only for intrathecal route
- ziconotide
  - derived from cone snail toxin
  - N-type voltage-gated calcium channel blocker
  - must be delivered intrathecally

Neuroablative procedure

e.g.
- nerve blocks
- thalamotomy
- cordotomy
predominantly deployed in the terminal phase of cancer
- where the balance of risks and benefits is altered
- potential adverse effects more acceptable

References

Cancer Survivors and Cancer Pain - BJA Ed