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Cancer pain - Specific applied knowledge/mechanisms (3.6.7 - 3.6.14)

Updated: Mar 7, 2022



Biological mechanisms for:


Solid-organ pain

  • Expansion can cause pressure on surrounding organs

  • Tumour infiltration in nerve plexuses and damage to nerve tissues can cause local neuropathic pain

  • Local and systemic inflammatory responses with pro-inflammatory cytokines can facilitate and sensitise pain transmission

  • Cancer cells may directly invade mechanically sensitive tissues

  • Tumour cells within the immune system can directly release factors such as endothelin, prostaglandins, and TNFalpha which excites or sensitises local nociceptive primary afferents

  • Tumours often increase the local acidic environment causing local acidosis and triggering chemoreceptors

  • Proteolytic enzymes released by tumour cells can damage sensory and sympathetic nerve fibres directly causing neuropathic pain

  • Distortion of the capsule of solid organs can cause localised pressure nociceptive noxious stimuli

  • Local pressure effects can cause necrosis of solid organs or occlude blood vessels leading to ischaemia



Hollow viscus pain

  • Stretching of hollow viscera can cause local stretch receptors to fire and trigger pain

  • Distension, impaction, ischaemia, ulceration, inflammation, or traction can all cause problems

  • Obstruction particularly can cause local ischaemia increasing intraluminal pressure and releasing pronociceptive mediators exacerbating the pain

  • Obstruction of tubes such as within the pancreas can contribute to further secretion pressure complications

Cancer direct effects upon bone (invasion, compression, metastases)

  • Metastatic bone pain can cause pain through the infiltration of sensory neurons that innervate the bone marrow

  • Alterations in normal bone turnover with activation of the RANK system can increase local bone acid environment and cause bone breakdown through osteoclast activation

  • The bone may lose mechanical strength leading to fractures and pressure complications

  • Mechanical pressures on the periosteum may be a major source of pain

  • Bone is highly innervated by C fibres which can be triggered by an inflammatory infiltrate from cancer cells

Indirectly related to cancer (pressure areas, herpes zoster)

  • Rapid weight loss, muscle hypercatabolism, immobilisation or increased muscular tension case muscular pain

  • Bone metastases can cause local muscle spasms

Related cancer treatments

  • Neuropathy can occur from chemotherapy and radiotherapy

  • Chemotherapy-associated neuropathy arises from disruption of tubulin function with the release of cytokines resulting in degeneration of sensory neurons and sensitisation of primary nociceptive afferents

  • Radiotherapy can cause tissue fibrosis with nerve compression and microvascular obstruction of the nerve supply. Nervous tissue compression or lesion can further contribute to central sensitisation

 

3.6.8 - Discuss how anti-cancer drugs (particularly those that affect the P450 system) may affect analgesia


It is estimated up to 1/3rd of cancer patients experience drug-drug interactions (DDIs)


The most significant interactions are:

  • Cytochrome P450 enzymes

  • Efflux pump p-glycoprotein

  • Protein-binding displacement (usually off albumin or alpha-glycoprotein)

Tyrosine kinase inhibitors are used in CML

Tamoxifen is a substrate for multiple C450 enzymes


Opioids

Most medications used to treat cancer undergo metabolism by the CYP450 system

The least effected opioids are Morphine, Hydromorphone, oxymorphone, and tapentadol

HOWEVER avoid Tramadol, codeine, oxycodone, and methadone


Antidepressants

Duloxetine, Venlafaxine, and TCAs may have altered effects in the setting of chemotherapy

Exactly what these are is difficult to state


NSAIDs

Surprisingly can be a big problem. NSAIDs reduce the renal excretion of some medications such as methotrexate

NSAIDs may also increase the risk of thrombocytopaenia

Celecoxib is a 'use with caution'

Aspirin may also cause problems and should be avoided







Chemotherapy drugs also often increase the risk of prolonged QT. This can exacerbate any prolonged QT with other drugs such as TCAs.


References:



 

Discuss analgesic benefits of:

  1. Chemotherapy

Can't find anything specifically on this!

  • Direct cancer size/tissue reduction

Radiotherapy

  • Radiotherapy is specifically used in bone metastases. Bone metastases are identified in up to 70% of patients with advanced cancer.

  • The exact mechanism of radiation-induced pain relief is unknown.

  • Likely from stimulation of ossification, diminishing osteoclasts activity, and killing cancer cells decreasing tumour burden

  • While it can initially cause a pain flare, it can significantly reduce ongoing pain from metastases.

  • It has been shown to increase the quality of life particularly in palliative care settings

  • Palliative radiotherapy provides pain relief in a median of 2-3 weeks for 60% of patients

  • When pain recurs, retreatment can be considered at least 4 weeks after initial to assess response

  • It can reduce the complications of obstruction such as dysphagia from oesophageal cancer

  • It can reduce the risk of spinal cord compression and can improve neurological function

  • Brain metastases can be addressed to reduce complications such as seizures, focal neurology, and symptoms of raised intracranial pressure


The main side effects of radiotherapy include:

  • Irradiation of the bowels (nausea, vomiting and diarrhoea)

  • Fatigue is at least 2/3rds of patients

  • Long term side effects are rare

  • Skin - sunburn type effects

  1. Hormone therapy

  • Antiandrogen therapies in prostate cancer can result in dramatic pain relief with a response rate of over 90%

  • Responses in metastatic breast cancer are generally slower and additional pain relief therapies are required

  • Hormone therapy may induce acute new activity in bone leading to acute pain flares

 

3.6.10 - Discuss biological mechanisms contributing to:


Post-chemotherapy pain specifically

  1. Chemotherapy-induced peripheral neuropathy

  • These are induced specifically by chemotherapy agents for cancer

  • There can also be paraneoplastic, immune-mediated, or neoplastic neuropathies

  • Painful, a dose-limiting side effect that will increase in prevalence with increased cancer prognosis

  • 30-40% of patients receiving neurotoxic chemotherapy will experience these symptoms

Particular problem chemotherapy agents include:

  • Taxanes

  • Platinum drugs

  • Vinca alkaloids

  • Thalidomide

  • Bortezomib

  • (Cyclophosphamide and methotrexate can cause it but this is rare)

Certain routes of administration of drugs can cause more problems (e.g. intrathecal MTX), dose, duration and pre-existing risk factors e.g. previous neuropathy and/or alcohol, diabetes etc.


Symptoms of CIPN typically start in the first 2 months of treatment and progress while therapy is ongoing, and then stabilise when ceased


ALWAYS consider other causes (particularly as they may be reversible)

  • Metabolic and endocrine-related neuropathies are possible. They can also be associated with increased risk - such as diabetes

  • Paraneoplastic neuropathies usually start at the onset of cancer - not the onset of treatment

  • Paraproteinaemias should be considered

  • Rarely, direct neoplastic infiltration can occur e.g. leukaemia

  • A bone marrow transplant can also be associated particularly triggering related neuropathies such as Guillian-Barre and CIDP

Pathophysiology

  • Neurotoxic effects on neurons - Sensory > motor or autonomic

  • Can be anatomical or physiological changes in nature

  • Neuropathic pain is likely from peripheral nerve hyperexcitability (via bioenergetics and ion channel expression) and central sensitisation

  • There may be involvement of glial cells - but this is unclear

The majority of signs and symptoms is from damage to dorsal root ganglion neurons or their axons. This can lead to sensory loss, acral (extremities) pain, and possibly sensory ataxia


Motor, autonomic or cranial nerve symptoms can occur however this is rarer.


Axonal damage is typically a 'dying back' neuropathy.


Development of CIPN indicated dose reduction or discontinuation of agent.

NB! Electrophysiology is NOT a good guide of patient symptoms or prognosis It can be used to help differentiate between sensory neuronopathy, length-dependent sensorimotor neuropathy, or small fiber neuropathies.


Prevention

  • There are no current preventative treatments for CIPN

  • Confusing why cancer drugs, designed to attack rapidly dividing cells, attack neurons that are not changing

  • Preventative strategies should NOT hamper the cancer-fighting effects of a chemotherapy drug

  • Risk factor modification is difficult - the only associated known factor is diabetes. Genetic factors are likely important.

Treatment

  • The primary treatment is ceasing the offending chemotherapy agent

  • Only duloxetine has been shown to help neuropathic pain in established CIPN (Nortriptyline, gabapentin, lamotrigine, topical amitriptyline/ketamine, topical baclofen/amitriptyline/ketamine - were also tested).

  • Novel electrostimulation therapies have shown early promise but require further study


References:

Staff, N. P., Grisold, A., Grisold, W., & Windebank, A. J. (2017). Chemotherapy‐induced peripheral neuropathy: A current review. Annals of Neurology, 81(6), 772–781. https://doi.org/10.1002/ana.24951


Mucositis

  • Mucositis can occur anywhere from the mouth to anus and symptoms occur in the affected site

  • Occurs in 20-40% of patients receiving chemotherapy for solid cancers and typically occurs within 5-14 days of receiving chemotherapy

  • Radiation-induced mucositis occurs in up to 91% of patients with head and neck cancer

  • Fluorouracil, methotrexate, and etoposide are at worse risk

  • They are at twice the risk of developing infections and four times the risk of death than patients who do not develop mucositis

Pathophysiology

Cytotoxic damage to rapidly dividing submucosal basal cells with epithelial damage

Radiation-induced mucositis is damage toe epithelial cells exposed to radiation


5 Stages:

  1. Initiation - Radiation and/or chemotherapy causes cellular damage --> promotes reactive oxygen species formation within the basal epithelium and submucosal cells (mucosa is grossly normal at this time)

  2. Primary damage response - Cellular damage activates p53 and nuclear-factor KB (NFKB) propagating the damage response

  3. Signal amplification - NF-KB causes activation of inflammatory cytokines TNFalpha, IL1, IL6 --> tissue damage and death (mucositis is now subclinical or subtle)

  4. Ulceration - Lesions in the mucosa become apparent - high risk for bacterial colonisation and infection

  5. Healing - Cessation from ongoing tissue damage that initiated the mucositis

Risk factors

  • The dose, duration, and type of chemotherapy/radiation therapy used

  • Smoking

  • Poor oral hygiene

  • Younger age

  • Female sex

  • Pretreatment low nutritional status

  • Pretreatment neutrophil counts

Before chemotherapy - a full mouth examination is required. If concerns, referral to a dentist is important

Patients should then be educated on what to watch out for


Preventative measures - Chemo and Radio

  • Brushing with a soft toothbrush twice a day, flossing daily, and rinsing with simple solutions 4 times daily is recommended

  • Dental treatment aggressively before chemotherapy can reduce the risk of mucositis by >25%

  • Cryotherapy or ice chip therapy for 30 mins before some infusions can help

  • Mucoadhesive hydrogel rinses can help prevent - but not confirmed in studies

Preventative measures - Radio specific

  • Dietary modification to avoid starchy, acidic and sharp foods

  • Honey swish and spit before radiation

  • Mucoadhesive hydrogel rinses

  • Benzydamine mouthwash (if only radio)

  • Zinc supplements maybe

Assessment of a patient with mucositis

  • Level of pain

  • Tolerated oral intake

  • Secondary infections

  • Bleeding risks

  • Systemic infection signs e.g. fevers

Oral examination is important

CBC can help for infection complications particularly in the setting of neurotropaenia

Metabolic panel for end organ damage should be assessed

There is a 1-5 grading system


Management - Chemotherapy related

Uncomplicated mucositis is generally self-limiting

  • Bland rinses and topical anaesthetics such as 2% viscous lidocaine swish and spit

  • Modify diet to avoid rough and sharp foods

  • Avoid alcohol and tobacco

  • Treat pain with 2% morphine mouthwash swish and spit in head and neck cancers receiving chemoradiotherapy

  • Consider admission to hospital for analgesia requirements or infection risks

  • Use patient-controlled analgesia with morphine

  • Transdermal formulations can be used

  • Normal saline or sodium bicarb solutions can help in mild cases

  • Chlorhex / topical antimicrobials are NOT recommended

Intestinal Mucositis

90% of patients receiving chemotherapy will experience GI distress

Up to 7.5% may die from these complications alone

Symptoms include nausea, vomiting, diarrhoea, and pain


Adequate hydration is essential and potential for transient lactose intolerance and bacterial pathogens should be considered


Prevention

Radiotherapy

  • Sulfasalazine 500 mg orally twice daily can help

  • Amifostine (may protect by scavenging free radicals)

  • Ranitidine or omeprazole can help in some settings

Treatment

Sucralfate enemas may help if rectal bleeding

Octreotide can help with diarrhoea


Reference:

Brown, T. J., & Gupta, A. (2020). Management of cancer therapy–associated oral mucositis. JCO oncology practice, 16(3), 103-109.


Sougiannis, A. T., VanderVeen, B. N., Davis, J. M., Fan, D., & Murphy, E. A. (2021). Understanding chemotherapy-induced intestinal mucositis and strategies to improve gut resilience. American Journal of Physiology: Gastrointestinal and Liver Physiology, 320(5), G712–G719. https://doi.org/10.1152/ajpgi.00380.2020

 

Post-radiotherapy neuropathic pain

Radiotherapy can directly damage CNS structures --> Focal radionecrosis

Radiation primarily effects white matter of the brain and spinal cord

Produces necrosis and vascular injury with also axonal and oligodendrocyte loss with gliosis and demyelination

Oedema, mass effect, increased ICP, and cognitive dysfunction are also observed


Can damage peripheral structures - typically brachial and lumbosacral plexopathies or myelopathy


Effects can be exacerbated if patients use radiotherapy and chemotherapy


NB: Pain from tumour-involved plexopathies is typically earlier and more severe than with pain from radiotherapy


Lumbosacral plexus injury may be from intracavitary radium implants for carcinoma of the cervix. Can also be from post-radiotherapy fibrosis or from cancer infiltration


Pain is an early symptom in 15% of patients suffering from post-radiation myelopathy

Can be sub-acute and present like a transient demyelination. Often occurs one to several months after irradiation and usually involves the cervical spinal cord. Often affects dermatomes below level of damage.


Radiotherapy may be associated with long term complications including:

  • CNS - Cognitive impairment and neurosensory impairment

  • Cerebrovascular disease risk

  • Hormonal issues related to pituitary failure/insufficiency and thyroid issues and diabetes

  • Lungs - Pulmonary fibrosis

  • Heart - AMI and cardiac complications

  • Bone growth plate problems

  • Male infertility

  • Second malignancy - High!

Radiation-induced neuropathy

Thought to be related to microvascular injury then radiation-induced fibrosis

Likely peripheral nerves also have electrophysiological and biochemical changes leading to axonal injury and demyelination


Risk factors:

Treatment factors:

  • Surgery and LN dissection with radiotherapy

  • Neurotoxic chemo at the same time

Patient factors:

  • Young or advanced age

  • Obesity

  • Hypertension

  • Diabetes Mellitus

  • Hypercholesterolaemia

  • Combined peripheral neuropathy

  • Arteritis risks

  • Collagen vascular diseases

  • Hypersensitive patients

Symptoms may develop further down in time

Radiation induced brachial plexopathy - progressive injury in the axillary-supraclavicular ipsilateral node volume after RT for breast cancer

Can come on months to years after RT

Classically begins with subjective paraesthesia or dysaesthesia which decraeses with development of hypoaesthesia and anaesthesia

Tinel's sign can be triggered

Neuropathic pain is rare and moderate

Motor weakness is progressive


RIPN treatment is with:

  • Non-opioid analgesics

  • Benzodiazepines

  • TCAs

  • Anti-epileptics

  • Vitamins B1-B6 can be used (but no real evidence)





Reference:

Delanian, S., Lefaix, J. L., & Pradat, P. F. (2012). Radiation-induced neuropathy in cancer survivors. Radiotherapy and Oncology, 105(3), 273-282.


(Plexopathy is a disorder of the network of nerves in the brachial or lumbosacral plexus. Symptoms include pain, muscle weakness, and sensory deficits (numbness)).


(Myelopathy is an injury to the spinal cord due to severe compression that may result from trauma, congenital stenosis, degenerative disease or disc herniation. The spinal cord is a group of nerves housed inside the spine that runs almost its entire length)

 

Define the difference between incident pain and incompletely relieved persistent pain

Breakthrough pain (BTP) is a transient exacerbation of pain that occurs either spontaneously or in relation to a specific trigger - despite relatively stable background pain relief

Pain recurring shortly before next dose of regular analgesia is called 'End-of-dose' pain


BTP two types:

  1. Predictable (incident) pain - caused by weight-bearing and/or activity which may or may not be in the same area as background pain

  2. Unpredictable (spontaneous) pain - Unrelated to movement or activity (e.g. colic pain)

BTP often has a rapid onset (median 3 minutes - ranging from 1-30 mins) and relatively short duration (median 30-180 mins)

Common in both cancer and non-cancer patients

BTP may be functional (e.g. tension headache) or pathological.

It may also be nociceptive or neuropathic


BTP can significantly impact upon quality of life

Pain on movement is the most common

May also be visceral and can be associated with autonomic changes also in that setting. Antimuscarinics are the mainstay of treatment in this setting

Can be caused by other cancer factors such as cachexia leading to nerve compressions


Management

Commonly 1/6th of the daily opioid dose (4 hrly) is used for opioids.

Individual titration is then required

Fentanyl breakthrough doses have NOT been shown to be related to background pain relief

The oral morphine dose can NOT be relied upon unless the background is morphine also. Otherwise, best to start with 5-10mg of morphine and titrate


There may be an argument for using different types of opioids for background and breakthrough pain - however studies are lacking


Neuropathic pain can also cause BTP. Consider other agents and/or clonazepam injections

Procedure pain can be treated with ketamine


S/L fentanyl is available in different formulations - designed to slow down absorption slightly

2/3rds of swallowed fentanyl will be eliminated by intestinal or hepatic first pass metabolism


Reference:

Zylicz, Z. B. (2013). Critical Appraisal of the Breakthrough Pain in Cancer. In Cancer Pain (pp. 121-130). Springer, London.

 

Discuss oncological emergencies


Acute spinal cord compression


  • Usually from a tumour compressing the dural sac

  • Most commonly with breast cancer though also MM, lymphoma, lung cancer and prostate

  • Develops in 5% of patients and can cause paralysis if treatment delayed by even a few hours

  • Most common presenting symptom is new onset back pain worsened when lying down - these symptoms MUST be evaluated until compression is ruled out

  • Pain on percussion of vertebral bodies is characteristic of this condition

  • Pain is often associated with more motor than sensory issues

  • Pain is progressive and then later cauda-equina like symptoms can develop

  • Treatment is generally surgical with radiotherapy as an adjunct


Life-threatening increased intracranial pressure


  • Presentation will vary depending upon the location of the CSF occlusion. The most common presenting symptoms are headache, seizures, stroke, and focal neurologic dysfunction

  • Other specific findings include nausea, vomiting and diplopia from abducens nerve palsies.

  • Cushing response (wide-pulse hypertension, bradycardia, and rapid resp rate - are late signs).

  • If not managed appropriately, elevated ICP can rapidly lead to irreversible neurological deficits

  • Usually, metastases go through blood vessels and lodge in watershed regions and grey-white matter junctions

  • ICP is commonly from direct pressure of the tumour mass as well as brain oedema induced by neoplastic impairment of the BBB

  • Treatment is commonly by glucocorticoids to reduce local swelling and compression. Mannitol and hyperventilation can be used in severe cases. Radiotherapy to the whole brain, chemotherapy or stereotactic radiation surgery can be considered.


Reference:

Jafari, A., Rezaei-Tavirani, M., Salimi, M., Tavakkol, R., & Jafari, Z. (2020). Oncological emergencies from pathophysiology and diagnosis to treatment: a narrative review. Social Work in Public Health, 35(8), 689-709.


Acute bowel obstruction and perforation of a viscus

  • May be caused by either intrinsic or extrinsic compression. Some tumours such as pancreatic, stomach, are more likely to disseminate into the the peritoneum and cause mechanical obstruction. They can also impair bowel motility by invasion of the coeliac plexus directly.

  • Medical management - GI decompression with a NG tube, hydration, control nausea and vomiting.

  • Octreotide ban is used to try and help symptoms of malignant bowel obstruction by reducing secretions.

  • Anticholinergics and glucocorticoids can also be considered.

  • Surgery can be considered in late settings.


Hypercalcaemia


Occurs in 10-30% of patients with cancer - Calcium > 2.63mmol/L

Usually multiple myeloma and breast cancer - but can occur with SCC

Three main causes:

  • Humoral (such as increased parathyroid hormone-related hormone or Vit D) (80%)

  • Bone invasion and osteolysis (20% of cases)

  • Rare = Immobilisation, medications, parathyroid tumour

Symptoms include mental function issues, weakness, anorexia, thirst, constipation, nausea, vomiting, decreased urine and coma

Treatment is fluid rehydration, diuresis with frusemide

Bisphosphonates may help

NB: It is a bad prognostic sign - death median survival 35 days


Long bone fracture

  • Manage as per fracture

  • Pathological fractures are a bad prognostic sign

  • Adjuvant radiothreapy can be tried. Fixation if required. Osteoclast inhibitors can be tried.

 



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