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:
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
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
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:
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)
Primary damage response - Cellular damage activates p53 and nuclear-factor KB (NFKB) propagating the damage response
Signal amplification - NF-KB causes activation of inflammatory cytokines TNFalpha, IL1, IL6 --> tissue damage and death (mucositis is now subclinical or subtle)
Ulceration - Lesions in the mucosa become apparent - high risk for bacterial colonisation and infection
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:
Predictable (incident) pain - caused by weight-bearing and/or activity which may or may not be in the same area as background pain
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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