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What is pain?
An unpleasant and emotional experience with actual or potential tissue damage (or described in terms of such damage). There is acute pain (<3 months) and chronic pain (>3 months).
Define nociceptive pain.
Produced by nociceptive stimuli which causes or has the potential to cause tissue damage. There is external and internal nociceptive pain/damage.
Describe external nociceptive damage.
From trauma to the skin that can extend to underlying tissue. Pain relief is easy to achieve with mild analgesics like NSAIDS (non-steroidal anti-inflammatory drugs).
Describe internal nociceptive damage.
Pain from internal damage like fractures, surgery or diseases. It’s treated by removing the cause of damage and more powerful opioid analgesics.
Define neuropathic pain.
Caused by injury or disease to the nervous system rather than peripheral tissue. It’s often chronic and hard to treat (complex aetiology, lack of knowledge of underlying mechanisms) There is peripheral neuropathic pain and central pain syndromes.
Describe peripheral neuropathic pain.
It’s from damage to the peripheral nervous system (eg. crush injuries). It feels like it comes from body parts that affected nerves supply, often burning or shooting pain that can lead to hyperalgesia and allodynia.
Describe painful diabetic neuropathy.
Degeneration of unmyelinated axons from hyperglycaemia or infection. It causes numbness/burning pain in distal extremities that spreads proximally and becomes more severe. The longer the body’s axons, the more susceptible the nerves are to hyperglycaemia.
Describe central pain syndromes.
From damage to the central nervous system like spinal cord injuries, tumours or strokes. They cause intense, aching, shooting pain.
Define psychogenic pain.
Pain with no underlying pathology. After exhaustive examination and testing, it’s assumed that the pain is from a psychological disorder. It’s less common (diagnostic improvements, better medical imaging), usually causing headaches and abdominal/back pain.
Define referred pain.
A disconnection between the injury site and the pain’s location, caused by specific pathways and neural connections in the brain. It is mainly from neuropathic pain, where it feels like it comes from the body part that the affected nerve supplies (eg. MI pain shoots down the left shoulder/arm).
Define hyperalgesia.
Original tissue damage causes extreme sensitivity to pain because of an amplified neural response. Additional stimulation greatly enhances the pain.
Define allodynia.
A reduction in a person’s pain threshold such that pain is now produced by low-intensity (non-damaging) stimuli (eg. wearing a scarf around the neck causes excruciating pain referred to the face).
Define breakthrough pain.
Pain felt between regular analgesic dosing (mainly severe chronic pain).
Describe how the pain pathway is organized in the body.
Small patches of peripheral tissue that detect stimuli are connected to parts of the cerebral cortex by a 3 neuronal pain pathway. Large numbers of these pathways are arranged in parallel to ensure most body tissues are connected.
Describe the 3 orders of neurons making up the pain pathway.
1st order - Carries info from peripheral tissues to spinal cord
2nd order - Relays info from the spinal cord to many sites in the thalamus
3rd order - Conscious perception of tissue damage is transmitted from the thalamus to cerebral cortex (opposite side) to perceive pain.
Define nociceptors.
1st order neurons found in peripheral tissue (subpopulation of sensory neurons) that detect sensations and are selectively activated by high intensity stimuli. Tissue damage causes inflammation, transmits pain signals to brain.
Describe some substances that stimulate nociceptors and nerve endings.
Bradykinin, prostaglandin, serotonin and potassium stimulate nociceptors.
Mast cells release histamine, stimulates nerve endings, causes blood vessels to allow fluid to leak into extracellular spaces, increases swelling and pain.
Define endorphins.
Endogenous opioids made by the body, attaching to opioid receptors on cell membranes of afferent neurons to inhibit the release of excitatory neurotransmitters. Receptors are close to tissue/spinal cord pain receptors.
Describe the gate control theory of pain.
Theory that a “gate” mechanism in the dorsal horn of the spinal cord modifies the transmission of painful sensations from peripheral nerves to the thalamus and cerebral cortex.
Describe opioid receptor subtypes.
The main CNS receptors are called mu, kappa and delta. All receptors have analgesia and constipation effects (slows peristaltic movement).
Agonists (morphine) activate mu and kappa receptors
Antagonists (naloxone) antagonise all opioid receptors
Describe some undesired central effects of opioids.
Suppression of cough reflexes/respiratory center, sedation/sleep, tolerance, dependence, addiction, euphoria/dysphoria, miosis, N+V, hypotension and bradycardia.
Describe some undesired peripheral effects of opioids.
Decreased GIT motility, severe constipation, and sphincter muscle spasms (delayed gastric emptying, urinary retention).
Describe some adverse reactions from opioids.
Respiratory depression (death from acute toxicity), excessive sedation, tolerance, dependance, dysphoria, constipation, nausea and vomiting.
Describe how opioid overloads are caused by altered organ function.
In liver disease, the active drug accumulates, sensitive to depressant effects. Renal disease extends the half-lives of opioids that are excreted in active forms, and causes respiratory depression.
Define equianalgesic dosing.
Patients with adverse effects from one opioid can be switched to another. The dose is compared to morphine (10mg IM/SC or 30mg oral), quoted as equianalgesic. Assess pain level, adverse effects and tolerance on switch. The initial dose should be half of what’s indicated by comparing doses (tolerance from one drug won’t extend to the other).
Define drug tolerance.
A gradual decrease in a drug’s effectiveness if given repeatedly over time. Prolonged administration causes cellular adaptation, leads to tolerance and dependence. Tolerance develops to analgesia, sedation, N+V, not constipation.
Define adjuvant medications.
Used along with opioids or NSAIDS to enhance pain relief (eg. anticonvulsants, antidepressants or corticosteroids).
How do adjuvant medications help with neuropathic pain?
Tricyclic antidepressants (amitriptyline) and anticonvulsants like gabapentin or pregabalin are useful with opioids for cancer associated nerve pain. Corticosteroids (dexamethasone) relieve pain from swelling and space-occupying lesions (cancer growing in restricted spaces).
Describe the analgesic ladder.
Mild - Non opioid, paracetamol/NSAIDS ± adjuvants
Moderate - Opioid + non-opioid (codeine, tramadol, oxycodone) ± adjuvants
Severe - Opioid + non-opioid (morphine, oxycodone, hydromorph) ± adjuvants
Monitor closely for major adverse effects
Describe anaesthesia.
Causes a brief induced loss of sensation/awareness (induction, conduction, recovery) There is general anaesthesia, local anaesthetic and awake anaesthesia.
Define cancer.
Uncontrolled proliferation of abnormal cells that arise from any cell type (disease of uncontrolled hyperplasia). Normal cell replication processes become deranged, damaged cells survive and grow at uncontrolled rates beyond tissue boundaries, apoptosis is disabled (immortality).
Define benign tumours.
Well-encapsulated tumours, not spreading to lymph nodes or other structures. Compression causes adverse symptoms. Named with an “-oma” suffix.
Define malignant tumours.
More rapid growth rates, not well defined, invades blood vessels, lymphatics and other structures.
Define carcinoma.
Cancer starting in cells making up skin/tissue lining organs (eg. liver or kidneys).
Define sarcoma.
Cancer starting in bone or connective/supportive tissue (eg. muscle, cartilage, fat).
How does cancer act in children under 15?
Likely more treatment-responsive cancers, kids tolerate treatment better, many are long-term survivors or are cured (long-term management of treatment impacts are vital).
How does cancer act in older adults?
It’s more common, treatment efficacy isn’t age-dependent, based on physiological parameters for the person and cancer type (consider their current health, organ function and general preferences).
Describe proto oncogene and oncogene mutations.
Proto oncogene: Good, instructs cell to undergo mitosis when required.
Oncogene: Bad, promotes an uncontrolled, increased mitosis rate.
Describe tumour suppressor genes.
They analyse cells, halt mitosis in abnormal cells, identifies repair needs, signals the cell to undergo apoptosis if unable to fix damage. If mutated, it can’t halt mitosis, identify repair needs or signal for apoptosis to occur in damaged cells.
Describe DNA repair genes.
Contains the information needed to instruct cells to repair identified damage. If mutated, there’s no repair function/disrupted function, which increases mutation rates.
What are some characteristics of cancer cells?
They have autonomy, anaplasia, angiogenesis and metastasis.
Define cancer cell autonomy.
Independence from normal cellular controls (they can avoid apoptosis).
Define cancer cell anaplasia.
Differentiation/normal function loss (bone tumour —> New bone formation is rare).
Define cancer cell angiogenesis.
Malignant tumours induce vessel formation for nutrient transport, they secrete “vascular endothelial growth factor” to stimulate angiogenesis. Drugs like bevacizumab block this growth factor.
Define metastasis.
Cancer cells travel through blood or lymph to other body parts, mainly the liver, bone or lungs, settling in tissue and growing secondary tumours. After metastasis, treatment is ineffective.
Define metastatic cancer of an unknown origin.
In very advanced tumours with widespread metastases, there may be cells that are so undifferentiated that original tumour cells cannot be identified.
Describe the role of the immune system in fighting cancer.
It recognises some early stage cancers, suppresses/eliminates them, only effective against small numbers of cancer cells (larger groups go undetected). Immunosuppressive therapy increases the risk of cancer by decreasing immune system function.
How does chronic inflammation contribute to cancer development?
It promotes continued proliferation (eg. ulcerative colitis or Hep B and C increase development risk).
Describe viral causes of cancer.
Hep B and C lead to liver cancer, HPV leads to cervical cancer. Some viruses lead to cancer growth.
Describe bacterial causes of cancer.
H. pylori infects the stomach/duodenum lining (gastric carcinoma), promotes DNA mutation and chronic inflammation, can be treated with 10-14 days of antibiotics.
Describe the TNM system for clinically staging cancer.
Defined by tumour size (T), involvement of lymph nodes (N), and degree of metastasis (M).
Describe the 4 stages of cancer.
Confined to the organ of origin
Locally invasive tissue
Spread to regional structures (eg. lymph nodes)
Cancer has metastasised to distant sites in the body
What are some clinical manifestations of cancer?
Weight loss, fatigue, pain (in advanced cancers, mediated by cytokines, acts on peripheral/nervous systems), infection, anaemia and thrombocytopenia.
Define leukopenia and pancytopenia.
Leukopenia - Low white blood cell count (neutropenia - low neutrophil count)
Pancytopenia - Low count of all blood cell types (low RBCs, platelets, and WBCs)
How does infection occur in patients with cancer?
Poor immune function secondary to cancer/treatments. Treat it with granulocyte colony-stimulating factors (GCSF) like filgrastim to increase neutrophil counts.
How does pain occur in patients with cancer?
In advanced stages, caused by obstruction, stretch, pressure and inflammation.
Define cachexia.
Severe muscle wasting and emaciation, caused by anorexia and early satiety (full after few bites).
Describe tumour lysis syndrome.
A large release of breakdown products from tumour cells killed by chemo agents, causing severe electrolyte imbalances, hyperuricemia (high uric acid levels). Treat or prevent with allopurinol and therapeutic alkalinising agents.
Describe febrile neutropenia.
A 38+ degree temperature and a neutrophil count under 1×10^9 cells/L, give broad spectrum antibiotics within 30 minutes of diagnosis.
Describe cord compression.
Pressure on the spinal cord that causes tissue ischemia, it must be decompressed to prevent permanent spinal cord damage from occurring.
Define haematopoiesis.
Blood cell production in bone marrow. Haematopoietic stem cells (hemocytoblasts) in bone marrow are partially differentiated (committed to becoming a blood cell). Cytokines can undergo haematopoiesis and stimulate progenitor cell proliferation.
Define the function of erythrocytes.
They are responsible for tissue oxygenation.
Define haematocrit and haemoglobin (Hb).
Haematocrit - Volume of blood occupied by RBCs, expressed as a percentage or ratio between RBCs and whole blood.
Haemoglobin - A special protein in erythrocytes that carry O2 and CO2, with a 120 day lifespan where new cells are produced in bone marrow.
Define leucocytes and neutrophils.
Leucocytes - WBCs removing debris, defending against pathogens (involves neutrophils, basophils, monocytes, and eosinophils).
Neutrophils - Consists of 55% of total leucocyte count, protects against bacterial infection, main phagocytes of early inflammation processes.
Define anaemia.
A reduction in the oxygen-carrying capacity of blood from inadequate erythrocyte numbers (low haematocrit), insufficient Hb levels, lack of normal RBC production, excessive RBC destruction, or loss of bloo volume in haemorrhage.
How is anaemia clasified?
By size, red cell content and possible cause (eg. iron deficiency anaemia).
Microcytic (small), normocytic, or macrocytic (large)
Hypochromic (pale), normochromic
What are the clinical manifestations of anaemia?
Lack of oxygen-carrying capacity causes tissue hypoxia, fatigue, feeling cold, pallor, SOB, rapid HR, and dizziness.
What is a complication of anaemia?
Blood viscosity decreases (thin blood), causes a hyper-dynamic state (can lead to cardiac dilation if not corrected, where the heart must pump harder to maintain a normal cardiac output.
Define iron deficiency anaemia.
Microcytic, hypochromic cells from inadequate iron intake/absorption, increased iron requirements (growth), or excessive iron loss (GI bleeds). Kids, menstruating females, people with GI bleeds or coeliac disease are at higher risk. It’s treated by eliminating blood loss where possible, iron replacement therapy.
Define pernicious anaemia.
Macrocytic, normochromic cells caused by atrophic gastritis, a complete or partial gastrectomy, or the absence of intrinsic factor (protein), secreted in the stomach, needed for Vitamin B12 absorption. Defective cells die early (insufficient erythrocytes). It causes “lemon yellow” skin (pallor + jaundice from bilirubin build-up) and neurological abnormalities since Vitamin B12 is a coenzyme for some metabolic functions (growth, mitosis, myelin synthesis).
How is pernicious anaemia identified and treated?
It is mostly ignored until it reaches severe stages as symptoms are vague, developing over 20-30 years. It is treated with cyanocobalamin (Vitamin B12 replacement) via weekly injection until deficiency corrects, then monthly lifelong injections as intrinsic factor is not secreted by the stomach independently.
Define folate deficiency anaemia.
Macrocytic, normochromic cells. Folate is needed for DNA production with developing erythrocytes, so a lack of folate means cell contents don’t fully develop, causing a shorter than normal lifespan. Bone marrow also produces fewer RBCs. Pregnancy deficiencies cause neural tube defects in kids. It causes a malnourished appearance, cheilosis, and stomatitis, treated with supplements.
Define aplastic anaemia.
A failure of the bone marrow to produce blood cells due to exposure to drugs, radiation, chemicals, or infections. It is treated by removing the underlying causes, bone marrow transplants (long term cure).
Define haemolytic anaemia.
Abnormal destruction of erythrocytes from infection, autoimmune disorders, or haematological cancers.
Define renal anaemia.
Caused by kidney disease (cannot detect hypoxaemia and respond by producing erythropoietin). Insufficient erythropoietin levels cause low erythrocyte production.
Define post haemorrhagic anaemia.
Occurs from sudden blood loss that occurs to quickly for the body to produce replacement erythrocytes.
Define polycythaemia.
Excessive erythrocyte levels causing a high haematocrit and thicker blood.
What are platelet and coagulation abnormalities?
Abnormalities from excessive/insufficient haemostasis levels, caused by platelet formation alterations (thrombocytopenia), platelet function (loss of adherence or aggregation) or coagulation abnormalities (fibrin mesh).
Define thrombocytopenia.
Decreased platelet production or increased consumption from nutritional deficiencies, drugs/reactions, bone marrow infiltration, infections, autoimmune diseases, or increased consumption (heparin-induced thrombocytopenia). It causes a platelet count below 150×10^9/L, only considered if under this number. It causes bleeding from mucous membranes or under skin, purple discolouration.
Define heparin-induced thrombocytopenia.
An immune mediated adverse reaction where IgG antibodies bind to platelet receptors, activates aggregation, causing low free platelet numbers, manifests as thrombocytopenia and a higher thrombosis development risk. Stop heparin use, consider other anticoagulants, reverse with protamine sulfate.
Define coagulation disorders.
Deficiencies in 1+ clotting factors (low conversion into fibrin) from genetics (haemophilia, low liver clotting factor production), Vitamin K deficiency, or pathological conditions (irregularly triggered coagulation, detrimental clotting).
Define haemophilia.
An X-linked genetic abnormality causing deficiencies in clotting factor production. Haemophilia A is a Factor VIII deficiency. Expression is more common in males. Males will express, females carry. It causes recurrent bleeding, easy bruising, hemarthrosis, intracranial/abdominal haemorrhage, and prolonged bleeding. Treated with recombinant clotting factors via lifelong injections.
Define leukaemia.
A malignant blood/blood-forming organ disorder, causing uncontrolled proliferation of malignant WBCs, overcrowding bone marrow. Leukaemia blasts proliferate, causing proliferation of other cells to stop, decreased function of normal haemopoietic cells. Results in pancytopenia. Classed as myeloid/lymphoid and degree of differentiation (Acute = rapid, immature. Chronic = slow, differentiated).
Define acute leukaemia.
Proliferation of immature blast cells in bone marrow which “spill over” into blood due to a blockage in cell maturation and accelerated cell division. They aren’t functional and disease progression causes short survival times. Treat with chemo, bone marrow transplant, supportive measures (blood/platelet transfusions), and specific colony-stimulating factors.
Define chronic leukaemia.
Proliferation of differentiated cells. Patients have a longer life expectancy extending several years from the time of diagnosis.
Define acute lymphoblastic leukaemia (ALL).
Affects lymphoblasts, can arose from the B or T cell lineage. It causes bone marrow depression, fatigue from anaemia, bleeding from thrombocytopenia, and fever from infection.
Define chronic lymphocytic leukaemia (CLL).
Mainly B cell alterations, failure to grow into antibody-producing cells, failure to respond to helper T cell stimulation. It suppresses antibody production (infection risk), causes anaemia, thrombocytopenia, and neutropenia. Patients are mainly unaware of it until symptoms appear or diagnosis occurs via routine blood test.
Define acute myeloid leukaemia (AML).
Proliferation of myeloid blast cells including pro-erythroblasts, megakaryoblasts, myeloblasts, and monoblasts. These immature cells are found in bone marrow.
Define chronic myeloid leukaemia (CML).
Several forms of this can occur depending on the lineage of malignant cells (eg. whether erythrocytes, platelets, basophils, neutrophils, eosinophils or monocytes are affected). Patients have a longer life expectancy with this type of leukaemia.
Define lymphoma.
Proliferation of malignant lymphocytes in the lymphatic system (Hodgkin’s and Non-Hodgkin’s lymphoma). Lymphoma affects lymph nodes, not blood/bone marrow.
Define Non-Hodgkin’s Lymphoma.
From single cell gene mutations leading to a loss of proliferation control (mainly in people 50+). It starts as lymphadenopathy (abnormal), painless swelling, abdominal fullness, back pain, ascites, and leg swelling. It has extra-nodal involvement, prognosis is poorer but individuals can survive for long periods. Treat with chemo, corticosteroids, radiation therapy, stem cell transplant, rituximab (monoclonal antibody against antigen CD20 on B cells + chemo).
Define Hodgkin’s Lymphoma.
Presence of Reed-Sternberg (RS) cells, represents malignant lymph cell transformation. It causes an enlarged, painless lymph node, asymptomatic mass (direct lymph node invasion), intermittent fever, night sweats and fatigue. Extra-nodal involvement is rare, 75% of patients are cured. Treated with chemotherapy and radiation therapy.
Define multiple myeloma.
B cell bone marrow malignancy, causing uncontrolled cloning of plasma cells and diminished antibodies. 25% are asymptomatic, many systems are affected causing bone pain, fractures, infection, fatigue, renal failure, neuro problems, and hyper-viscosity syndrome. Clinical signs (CRAB) —> Calcium, renal function, anaemia, and bone lesions.
What is the treatment and possible complications for people with multiple myeloma?
It is incurable, aim to stop abnormal cell production, manage adverse effects. Use “novel agents” like thalidomide, lenalidomide, and bortezomib to destroy myeloma cells in bone marrow before stem cell transplantation occurs.
Complications include bone disease (cytokines are made, some stimulate osteoclasts to break down, releases calcium into the blood) and renal disease (free immunoglobin light chains circulate in blood/urine, damages renal tubules).
Define innate immunity.
Non-selective immunity that includes all parts of the immune system except those that recognise/remember foreign substances (general response). 1st line include skin, mucous membranes, vomit, and urine. 2nd line includes cells, chemicals, and processes activated when pathogens breach the 1st line (eg. phagocytes, NK cells, cytokines, swelling and fever).
Define phagocytes.
Types of WBCs/leucocytes that engulf and destroy pathogens (either neutrophils or monocytes that become macrophages). Neutrophils move to site rapidly in large numbers to start phagocytosis. Monocytes become macrophages when migrating to infection site (they are also antigen presenting cells).
Define adaptive immunity.
Selective 3rd line of defence (cellular/humoral immunity). It has a memory, gives long term protection against pathogens, making a fast 2nd response if identified twice (involves lymphocytes and antigen-presenting cells).
Describe the types of B lymphocytes.
They make antibodies that enter blood and react with antigens, differentiating into plasma or memory cells on exposure. Plasma cells secrete antibodies and bind to antigens, memory cells rapidly become plasma cells on 2nd exposure.
Describe the types of T lymphocytes.
They can be helper T cells (assists B/T cell activation), cytotoxic Ts (killer cells), regulatory Ts (prevents overactivation), or memory Ts (proliferates on 2nd exposure like memory Bs).
Define antigen-presenting cells.
They ingest antigens, travel to lymph nodes, gives antigens to naive T cells to induce an immune response (macrophages and dendritic cells).
