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Management of Cancer-associated pain (3.6.15 - 3.6.24)

Updated: Mar 7, 2022




Discuss different goals for a pre-terminal versus a terminal patient


Goals between pre-terminal and a terminal patient can be quite different

For example, a pre-terminal patient may retain significant function and quality of life which needs to be considered and maintained whereas for a terminal patient a focus on comfort, dignity and appropriate support through the dying process take priority


Terminal - End-of-life analgesia:

A full pain history is required

Pain assessment tools may be based more on behaviour than self-reported scores e.g. PAINad and Behavioural pain scale (BPS)

Surrogates are not very accurate at predicting severity of pain

Clinicians can think - "Would I be in pain in this situation?" to help guide treatment

Oral routes of medication become limited - preventing use of medications such as gabapentinoids, antidepressants etc.


Morphine is most commonly used and experience and evidence remains for it. Watch for renal failure

Fentanyl does not have active metabolites. Patches make it difficult to titrate. Breakthrough can be treated with transmucosal fentanyl

Hydromorphone can be used more safely in renal impairment concerns than morphine. Can be used subcut as volumes are smaller for stronger effect

Methadone - can be very effective but long and unpredictable half-life makes its use more difficult regarding risk of oversedation and respiratory suppression

Oxycodone can be used


Routes to consider include subcut, IV, transdermal, rectal, vaginal, or neuraxial


Opioids should be started with a morphine dose of 5-10mg Q4h in opioid naieve

In later doses, can consider opioid rotation.


IV 24 hr infusion is often required, though PCA can be used in patients who are still able to control this factor


Other medications to consider:

Parenteral lidocaine can be used in cases refractory to opioid use

Ketamine can be utilised

Interventional strategies such as alcohol, phenol, or glycerol neural blockade

Neurolytic coeliac plexus block can be performed in pancreatic cancer

Bowel obstruction requires decompression and control of secretions including anticholinergics (such as scopolamine) and octreotide

 

Discuss cancer therapies specific to pain


Radiotherapy

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

Exact mechanism of radiation-induced pain relief is unknown.

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

While it can initially cause a pain flare, it can significantly reduce ongoing pain from a 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 intercranial pressure


Main side effects of radiotherapy include:

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

  • Fatigue in at least 2/3rds of patients

  • Long term side effects are rare

  • Skin - sunburn type effects

Radiopharmaceuticals

Radiopharmaceuticals (RPT) are systemically or locally delivered pharmaceuticals that bind preferentially to cancer cells or accumulate at sites of these cells through physiological mechanisms. They deliver either β-particles or more potent α-particles.


These particles can be viewed on imaging to give a guide to specific targeting of the pharmaceutical to the specific cancer


Compared to other therapies, RPT has limited toxicity and effects can be seen rapidly - after a single or at most 5 injections.


Some agents have recently been approved for Beta emitters to be used against neuroendocrine cancers and phaeochromocytomas and alpha-emitters for prostate cancer.


In prostate cancer: Patient summary: In this report we reviewed the efficacy of bone-seeking radionuclides for treating bone pain from metastatic prostate cancer. Overall, treatment with bone-seeking radionuclides resulted in pain responses greater than 50-60%.


Reference:

Jong, J. M., Oprea-Lager, D. E., Hooft, L., de Klerk, J. M., Bloemendal, H. J., Verheul, H. M., Hoekstra, O. S., & van den Eertwegh, A. J. (2016). Radiopharmaceuticals for Palliation of Bone Pain in Patients with Castration-resistant Prostate Cancer Metastatic to Bone: A Systematic Review. European urology, 70(3), 416–426. https://doi.org/10.1016/j.eururo.2015.09.005


Sgouros, G., Bodei, L., McDevitt, M. R., & Nedrow, J. R. (2020). Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nature Reviews Drug Discovery, 19(9), 589-608.


Chemotherapy

Chemotherapy can be used in several key goal areas:

  1. Rare tumours it can be curative

  2. To Shrink tumours that then may regrow

  3. To eradicate micrometastatic disease

  4. Downstage tumours prior to surgery



Immune therapy

Immune therapies such as adoptive immune cell infusions have been associated with reductions in opioid consumption and pain intensity amongst patients with advanced cancer


Interestingly the analgesic effect of immune therapies may not be directly related to cancer tissue destruction - as studies where tumour did not shrink in size still lead to significant pain reductions and reduced opioid use in responsive patients.


The immune therapy may have a secondary mechanism affecting signalling between tumour cells and sensory nerves leading to anti-nociceptive properties.


Reference:

Amaya, F. (2020). Immunotherapy for the management of cancer pain. Annals of palliative medicine, 9(4), 1358-1360.


Surgery


There are limited indications for surgery specifically for analgesic benefit. Vertebroplasty can be used or pathological fractures of the vertebrae that do not respond to conservative therapies of medications, TENS, or steroid epidurals - can be considered for fixation by cemented vertebroplasty. Relief can be complete in around 80% of patients. Cement leak is the most common risk at 5%. Complications are rare, but serious.


Hormonal therapies

Aromatase inhibitors can cause the AI-induced musculoskeletal syndrome which is a substantantial problem leading to therapy discontinuation in 1 in 4 patients

 

Discuss management of acute pain in cancer patients


Diagnostic interventions

All interventional options should be considered within the framework of patient expectations, function, current therapeutics, and prognosis


Laboratory investigations can be utilised such as serum calcium to highlight bone pain in multiple myeloma or bony involvement from prostate cancer.


Tumour markers may be useful for marking progression of disease

Radiological investigations range from plain bone radiographs which may identify skeletal lesions - but only when 50% of the bony cortex has been destroyed can osteolytic lesions be seen.


CT and MRI are anatomical modalities and functional modalities include scitography (highly sensitive but not specific for bone lesions) and positron emission tomography (which commonly uses a radiolabelled isotope taken up by glucose-seeking tissues - thought to correlate with metabolically hungry tumour cells).


Reference:

Krajnik, M., & Zylicz, Z. B. (2013). Pain assessment, recognising clinical patterns, and cancer pain syndromes. In Cancer Pain (pp. 95-108). Springer, London.


Therapeutic interventions


Neurolytic Coeliac Plexus Block - Used for pancreatic carcinoma.

Pain afferents from high abdominal viscera (pancreas, liver, gallbladder, adrenal, kidney, and GI tract from GO junction to colic splenic flexure) are carried by nerve fibres entering coeliac plexus and splanchnic nerves. Anatomically it is next to the coeliac trunk. Can be from T12 to L2.


The coeliac plexus is formed from the greater (T6-9) and lesser (T10-12) splanchnic nerves


Alcohol (often 95%) is used on the coeliac plexus structures causing extensive tissue damage. It causes Wallerian degeneration with axonal disruption, retraction, and hydrolysis of the myelin sheath.


Outcomes are unclear with few well-performed studies. General studies suggest improved QOL and reduced analgesic requirement. A Cochrane study in 2011 suggested some superiority of pain relief over analgesic therapy with fewer adverse effects than opioids.


Hypogastric superior plexus block


The plexus receives fibres from the pelvic viscera.


Blockade can be performed for late stage cancer pain from pelvic organs. Limited studies suggest a reduction in painful symptoms and reduction in analgesic consumption in treated patients


Located in the retroperitoneal space under the aortic bifurcation at the level of L4-L5 Lumbar and first sacral bodies.


Combination of aortic plexus with 3rd and 4th lumbar splanchnic nerves and prolongs the inferior hypgastric plexus







Neuraxial infusions

Opioids can be delivered directly to opioid receptors in the spinal cord. Reduces the adverse symptoms of systemically administered opioids with significantly reduced doses


Recent randomised controlled trials of spinal infusions highlighted an overall improvement in pain relief and less drug-related side effects compared with medical therapy for fully implanted systems.


Morphine is commonly used +/- bupivacaine. Clonidine and ziconitide have also been used.


Percutaneous cervical cordotomy


The aim is to destroy the lateral spinothalamic tract

It is performed between C1 and C2 as the fibres are closely compacted in the anterolateral quadrant of the spinal cord


Often the resulting lesion lasts until the death of hte patient

Pain is abolished in approximately 80% of patients


Reference:

Schweiger, V., Polati, E., Paladini, A., & Varrassi, G. (2013). Interventional Techniques in Cancer Pain: Critical Appraisal. In Cancer Pain (pp. 231-247). Springer, London.


 

Discuss

  1. Post chemotherapy pain

The most common concern is chemotherapy induced peripheral neuropathy. This has been discussed in previous curriculum topics.

Hand-foot syndrome can occur with some chemotherapy agents - a rash on the hands and soles


  1. Post radiotherapy pain

Plexopathies

Delayed brachial and lumbosacral plexopathies have been described after radiotherapy - prevalence from 2-5%

Onset is usually 6 mths to 30 years after radiotherapy - peak onset 2-4 years

Opioids and adjuvant analgesics are recommended but not well studied


Osteoradionecrosis

This is a particular concern after head and neck radiotherapy

Theories are unclear but may involve radiation-induced osteomyelitis, hypoxic and hypovascular theory and fibroatrophic theory

Prevention involves restorative dentistry and radiation planning and smoking cessation

Treatments vary from 'watch and wait' through to radical surgical strategies

Hyperbaric oxygen is controversial


Radiation enteritis/proctitis

Cramping, nausea, vomiting. Pelvic inflammation can cause tenesmus, mucus discharge and bleeding


Reference:

Dhanda, J., Pasquier, D., Newman, L., & Shaw, R. (2016). Current concepts in osteoradionecrosis after head and neck radiotherapy. Clinical oncology, 28(7), 459-466.


Fractures

Pelvic insufficiency fractures can occur after prostate radiotherapy and gynaecological radiotherapy

Osteoporotic vertebral compression fractures can also occur

Radiotherapy to already weaknened bones such as in sarcoma is also clearly a risk for long bone fracture

Risk increases after 40 Gray


Abdominal and Pelvic pain

Chronic pelvic pain - persisting in the hips, groins or lower back are commonly described in cervical cancer survivors

Chronic abdominla pain can occur from transmural fibrosis and vascular sclerosis. These can cause functional changes that further lead to pain.

Toxicity to the bladder can cause a chronic cystitis

 

Discuss mucositis in children

Affects more than 3/4ths of patients undergoing chemotherapy

Can be from mild and painless tissue changes to bleeding ulcerations

Can increase infection risks and prevent chemotherapy continuation

Prevention is best through appropriate oral cares


Best options are antimicrobial mouthwashes, amino acid rinses and topical healing agents

May require hydration, caloric intake support, to relieve pain and prevent infection

Salt and bicarb mouth washes can be helpful

 

Outline changes in pain management when a patient can no longer


Swallow

Choose less invasive route of administration

- Buccal mucosal or oral first

- Subcutaneous or rarely IV

- Rectal

- IM almost never

- Intrathecal

- Nerve blocks

- Epidural


Subcutaneous: Button, Butterfly needle, Abdomen/thigh/upper arm


(Hypodermoclysis, which can also be called interstitial infusion or subcutaneous infusion, is the subcutaneous administration of fluids to the body, often saline or glucose solutions.)


Subcut analgesia includes: Hydromorphine, morphine, fentanyl

Morpine is 1:1 for IV/SC

Subcut agitation: Haloperidol, phenobarbitol, lorazapam

Nausea: Haloperidol

Terminal congestion: Scopolamine


Topical - Fentanyl, compounded NSAIDs, lorazepam gel

Rectal can be used. Long acting meds become immediate release!


Is unconscious

Likely to die within days


Similar rules apply as the above


Reference:

 

Discuss the following adjuvant analgesics in cancer pain


Bisphosphonates

Bisphosphonates are pyrophosphate analogues which bind to hydroxyapatite and inhibit osteoclast action

They may directly inhibit cancer growth and reduce skeletal related events (30-40% less)

50% of patients report clinically relevnt analgesic effects


Denosumab

Works in a similar way - however it is a RANKL antibody - helps prevent complications from prostate cancer, breast cancer, and other solid tumours. Decreases hormonal treatment loss. Osteonecrosis of the jaw is a feared complication.


Calcitonin

It is a hormone normally produced by parafollicular cells in the thyroid gland. It acts to reduce blood calcium - it is the opposing hormone of PTH

Calcitonin inhibits osteoclasts (reducing calcium in the blood stream)


Corticosteroids

Thought to provide analgesia through blockage of cytokine synthesis that contributes to both inflammation and nociceptiion

Analgesic benefits of corticosteroids are dose-dependent and they have limited duration of action

It also works in visceral pain by inhibiting neuronal nitric oxide gene expression


Ketamine

Ketamine is an NMDA antagonist anaesthetic agent. At subanaesthetic doses it can be used as a coanalgesic often with opioids. It can be particularly useful in neuropathic pain.

Ketamine crosses the blood/brain barrier and is metabolised by the liver with the CYP450 system

Cochrane review in 2012 showed two RCTs with ketamine addition to opioids for cancer pain. Both studies, administered IV or intrathecally, were effective in improving analgesia. Trials were small however.

 

Discuss the role of interventional procedures in the management of cancer pain


Neuraxial and intracerebroventricular administration of medications

Intrathecal drug delivery systems (IDDS) can play an important role in cancer pain. Early placement of IDDS in cancer patients with moderate to severe pain can improve pain control, decrease side effects, and even increase life expectancy.


Often a temporary intrathecal catheter is placed to assess pain relief and degree of side effects.

Main reasons to consider IDDS trials include:

- Establish the efficacy of analgesic response

- Create an initial dose estimation

- Assess a reduction in opioid-related side effects

- Determine individual tolerability (including psychological and expectations)


However there is a lack of data of correlated success with a trial leading to success with an implanted pump device


Commonly used medications include opioid, local anaesthetic and clonidine


Reference:

Khimani N., Narang S. (2019) Intrathecal Drug Delivery System Trialing for Cancer Pain Management. In: Gulati A., Puttanniah V., Bruel B., Rosenberg W., Hung J. (eds) Essentials of Interventional Cancer Pain Management. Springer, Cham. https://doi-org.ezproxy.library.sydney.edu.au/10.1007/978-3-319-99684-4_30


Neurolytic blocks - saddle and coeliac blocks

Chemical neurolysis is usually achieved with alcohol, phenol, or glycerol

It is typically only performed after a block has been proven successful??


Ethyl alcohol - Causes myelin loss and wallerian degeneration. Increased risk of spread to other tissues. Analgesic effect usually within 12 hours and can last weeks to months


Phenol neurolysis - Causes similar damage. Is hyperbaric. Has a local anaesthetic type effect and therefore commonly causes less local pain. Often mixed with glycerin to help prevent spread.


Coeliac blocks - Blocks the autonomic supply to the upper GI tract. Can help with pancreatic and upper GI malignancies. May be associated with improved survival. Usually alcohol is injected. Diagnostic block can be performed but efficacy is unclear


Saddle phenol block - Phenol glycerin is injected into the subarachnoid space from between the fifth lumbar and sacral vertebrae with the patient in the sitting position. It has poor selectivity for dorsal root ganglia so bladder and bowel disturbances may be associated. It is indicated for cancer pain in the anal and perineal areas.


Reference:

Iseki M. (2019) Saddle Phenol Block (Landmark Technique). In: Ohseto K., Uchino H., Iida H. (eds) Nerve Blockade and Interventional Therapy. Springer, Tokyo. https://doi-org.ezproxy.library.sydney.edu.au/10.1007/978-4-431-54660-3_69


Surgical procedures - Cordotomy

Can be used to treat unilateral pain occurring below the C4 dermatome

It is the lesioning, sectioning, or interruption of the spinothalamic tract

The LST will carry pain and temperature from the contralateral side of the body

It is performed percutaneously at the level of C2 (though sleep apnoea can be a problem)

Cancer pain control is said to be >95%

Complications include: weakness, hypotension, dysaesthesia, mirror image pain, ataxia, incontinience and sleep apnoea

it has a GRADE 1C for cancer pain and has the most evidence for ablative procedures.

 

Discuss complementary and alternative therapies in the setting of cancer pain


 

Discuss the evidence for cannabinoids in palliative care


Cannabinoids are derived from the cannabis plant that contains over 400 compounds and 60 cannabinoids. The primary psychoactive component is THC. The cannabinoid molecules interact with an endogenous system of cannabinoid-like ligands as well as multiple receptors in the periphery and centrally.


In the US, cannabinoids are approved only for chemotherapy-induced N&V and appetite stimulation in wasting illnesses. In some countries it has been approved for spasticity in multiple sclerosis. In Canada it has been approved for advanced cancer with opioid refractory pain.


Available data from controlled trials suggest cannabinoid-type drugs may be useful as multipurpose analgesics however few studies have been completed in cancer patients.


Two systematic review and two meta-analyses of RCTs for cannabis and cannabinoids have found some efficacy for chronic pain specifically neuropathic pain. However all trials had major flaws including very diverse population groups and very few hard cancer patients. Multiple formulations were used and bias and study sponsorship was high. Unsurprisingly results were variable.


Given the lack of high-quality evidence of efficacy despite many trials cannabinoids could only be considered in extreme circumstances balancing the low liklihood of benefit versus possible harms.


The faculty of pain medicine has specifically recommended against the use of medicinal cannabis products for patients with chronic non-cancer pain unless the treatment is part of a registered clinical trial.


This recommendation coincides with a statement from IASP saying there is a lack of sufficient evidence to endorse the use of medicinal cannabis to treat pain.


Palliative care Australia released a position statement in 2017 on cannabis products


The Australian TGA in their guidance document for clinicians published in 2017 concluded there is no robust data on long term harms for the use of cannabis products. There is no scientific data to support the use of medicinal cannabis products for chronic neuropathic pain


The TGA primarily considered a systematic review and meta-analysis of palliative care for patients with terminal cancer, late stage Alzheimer's and AIDS. The review included 13 studies including 9 RCTs and 4 observational studies. GRADE level of evidence revealed studies were moderate to very low quality. The systematic review concluded there was not difference in outcome for patients who received medicinal cannabis or placebo for patients with terminal cancer.


Final recommendation was for it only to be used after standard therapy was ineffective. THC may assist appetite however even this evidence is unclear.


Oromucosal spray - THC + CBD can be trialled as an adjunct if refractory to opioids and alternative analgesics.

Other routes of administration are controversial

There is no data on the benefits of CBD oil in any cancer pain


References:



 



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