8th January 2024

Adjuvant analgesia

Adjuvant analgesia is mentioned in step 1 of the WHO analgesic ladder. An adjuvant analgesic is a drug which was not initially marketed for pain but has some analgesic properties, making it useful in pain management. Some are broadly useful, whereas some are beneficial in specific pain syndromes.

Neuropathic agents

There are different agents which are preferred to opioids in the management of neuropathic pain. As discussed previously, patients with cancer often have more than one type of pain, and it is perfectly possible for neuropathic and nociceptive pain to co-exist within the same patient. Management of this can be difficult. Opioids do have some effect on neuropathic pain, so it is not unreasonable to follow the analgesic ladder and trial strong opioids first where there are multiple pains, particularly in cancer.

Clinical guidelines recommend the following escalation strategy where neuropathic agents are sought:

• Amitriptyline first line, 10mg at night, with slow titration to a maximum dose of 70mg.
• If ineffective, switch to gabapentin, 100mg three times a day, with titration in 300mg steps to 1200mg three times a day. This can be combined with amitriptyline if this has been partially effective.
• Duloxetine third line, 30mg a day slowly titrated to maximum 120mg.

We will go through the considerations of each drug in turn.

Amitriptyline

Amitriptyline is a tricyclic antidepressant (TCA) but is used at different doses for neuropathic pain than it is for depression. Neuropathic pain can be particularly troublesome at night, affecting sleep quality, which has a number of ramifications; amitriptyline helps sleep, hence its use as first choice.

Many drugs in palliative care can cause prolongation of the QT interval on ECG predisposing to potentially fatal arrhythmia such as Torsades de Pointes. Amitriptyline is one such drug, and the ECG must be checked prior to commencing therapy. Additionally, a history of arrhythmia, heart failure, or ischaemic heart disease would be a contraindication to amitriptyline.

Unfortunately, Amitriptyline is often not tolerated. Patients may experience delirium or sedation. There is also the risk of antimuscarinic side effects. If it is not tolerated, nortriptyline can be considered, but this would be guided by a specialist palliative care physician. Alternatively, patients may progress to the next step of treatment with gabapentinoids. Where patients have been on amitriptyline for more than 8 weeks, it must not be stopped abruptly.

Gabapentinoids

Gabapentin is the first choice in many guidelines, but many of you will also be familiar with pregabalin. They are classed as anti-epileptics, blocking presynaptic neurotransmitter release. Pregabalin has historically been a more expensive drug, but the difference is not as significant now. Pregabalin is advantageous as a twice-daily option, reducing tablet burden. Studies have shown similar efficacy for both drugs; local guidelines will play a role in choice.

Current guidelines recommend gabapentin as a second-line option for neuropathic pain (doses above). Pregabalin is recommended where there is a response to gabapentin, but side effects are intolerable. It is ordinarily commenced at 75mg twice daily. Dose reductions are recommended for frail patients or those with renal impairment.

Common side effects include drowsiness and confusion. As mentioned in ‘respiratory depression,’ gabapentinoids are a risk factor for opioid-induced respiratory depression, and studies have shown patients are more likely to suffer an opioid-related death when also taking gabapentin. Given the complex nature of cancer pain control, it is common for patients to be co-prescribed gabapentinoids and opioids. These patients must be closely monitored and have doses cautiously titrated.

Duloxetine

This is fourth line for neuropathic pain after trialling a combination of TCA and gabapentinoid. Earlier treatment is indicated in pain caused by diabetic neuropathy, for which it is specifically licensed. A serotonin noradrenaline reuptake inhibitor, it has shown a good effect in painful peripheral neuropathy – both related to diabetes and chemotherapy. It is commenced at 30mg daily and titrated to a maximum of 120mg a day.

Steroids

Corticosteroids are used for a number of symptoms in the treatment of cancer. Glucocorticoid steroids have greater anti-inflammatory properties. By reducing oedema at the site of the tumour, they play an important role in cancer pain management. The evidence for their usefulness is based on clinician experience rather than extensive trial data. In practice, they are widely used for a number of different pain syndromes:

• Nociceptive pain: cancer can exist in enclosed spaces. In hepatomegaly, the liver capsule may stretch and cause pain. The anti-inflammatory effect can reduce this stretching and give pain relief.
• Neuropathic pain: reducing inflammation can improve ongoing compression or injury to the nerve from the malignancy – for instance, in spinal cord compression.
• Bone pain: dexamethasone is often used in treatment of metastatic bone pain to prevent worsening during radiotherapy treatment.
• Obstruction: reducing the inflammation from a malignant bowel obstruction, for instance, can increase the size of the bowel lumen and alleviate symptoms and pain.

Side effects

The utility of steroids is balanced against their many side effects. Courses of steroids may be given in short ‘pulses’ to avoid developing these. Below is by no means an exhaustive list, and a more thorough discussion of steroid side effects can be found elsewhere. However, some important things to bear in mind include:

• An increase in blood sugars is seen. Blood sugars should be checked regularly and at least daily if in a healthcare setting. In pre-existing diabetics, control may be worsened.
• Steroids are associated with an increase in adverse gastrointestinal events, including ulceration and GI bleeding. A proton pump inhibitor should be started alongside higher doses of steroids as such.
• Psychiatric disturbances, ranging from depression to paranoia, are possible. The steroid should be stopped to resolve this.
• Steroids are immunosuppressants, so long-term use may be associated with opportunistic infections.
• Avascular necrosis of bone can cause pain and loss of function within the affected area.
• Osteoporosis may cause pathological fractures, affecting pain and function. Bone protection strategies should be considered in those on long-term steroids.
• Recurrent or long doses must not be stopped abruptly due to the risk of hypoadrenalism.

Benzodiazepines

Benzodiazepines are typically used in palliative care for agitation, anxiety, insomnia, or seizures. They are GABA receptor modulators, causing presynaptic inhibition. This can have a function in neuropathic pain, where clonazepam is an option. This would be a decision taken by a specialist however.

In skeletal muscle spasm and spasticity, benzodiazepines may be used, particularly at the end of life. However, baclofen is preferred for both indications, particularly where longer courses are needed.

Bisphosphonates

Bisphosphonates include pamidronate and zoledronic acid. They inhibit the activity of osteoclasts, reducing the breakdown of bone. As such, they are used in hypercalcaemia and cancer-related bone pain.

They can be used prophylactically orally or IV to prevent bone pain or fractures in patients with breast cancer and myeloma. Treatment of bone pain, however, is given IV due to poor bioavailability orally. It is generally used where there is widespread metastatic disease, as radiotherapy is preferred where this is localised. Pain relief can take about two weeks and has a variable duration dependent on the agent chosen.

Patients may suffer transient worsening of bone pain following administration of bisphosphonates. Up to 50% of patients develop a viral-like illness, including fevers, 48 hours after administration. For the exam, the most significant side effect to be aware of is the development of osteonecrosis of the jaw. This is more common in those with previous dental procedures and poor dental health – so a dental review may be required before administration.

Antispasmodics

Buscopan (Hyoscine butylbromide) is available over the counter in the UK. This is an antimuscarinic. It has anti-secretory properties, which can be used for secretions, and antispasmodic properties, which help manage smooth muscle spasm-type pain in the GI tract. This can help with colic, a deep, twisting pain which comes in waves.

Oral bioavailability is poor, but Buscopan can be given subcutaneously, either as required or in a syringe driver.

Nerve blocks

There are several different interventional pain management strategies. These are complex and performed comparatively rarely. For the purpose of the exam, being aware of the options for nerve blockade will be sufficient.

Nerve blockade involves the injection of drug (typically alcohol or phenol) into a part of the peripheral nervous system to reduce pain. This is considered where medications have not controlled the pain, and a nociceptive pathway is clearly identified. It is useful in visceral nociceptive pain, and intervention prevents nociceptive activity in the nerve. This isn’t an option in neuropathic pain, where the nerve is already damaged.

Celiac plexus block

The celiac plexus innervates the upper abdominal organs and is frequently implicated in pain related to pancreatic cancer. The plexus is accessed either percutaneously with CT guidance or endoscopically under ultrasound guidance. This is a safe procedure, and data suggest it provides excellent pain relief.

Superior hypogastric block

This is an option for visceral pelvic pain, often associated with pelvic malignancies. This is usually accessed intraoperatively or through CT guidance.

References

• Twycross R, Wilcock A, Howard P. Palliative Care Formulary 6th edition 2017. 210-302
• Twycross R, Wilcock A. Introducing Palliative Care 5th edition 2016. 356-374
• Watson M, Lucas C, Hoy A, Back I. Oxford Handbook of Palliative Care 2005. 228-229.
• Greater Manchester and Eastern Cheshire Strategic Clinical Networks. Palliative Care Pain & Symptom Control Guidelines for Adults 2019 [Internet] [Cited 1/3/2022]. Available at: https://gmmmg.nhs.uk/guidance/clinical-guidance-and-pathways/
• UpToDate [Internet]. Uptodate.com [Cited 2/3/2022]. Available from: https://www.uptodate.com/contents/cancer-pain-management-role-of-adjuvant-analgesics-coanalgesics?search=cancer%20pain%20management&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2#H18
• UpToDate [Internet]. Uptodate.com [Cited 2/3/2022]. Available from: https://www.uptodate.com/contents/major-side-effects-of-systemic-glucocorticoids?source=history_widget#H11
• UpToDate [Internet]. Uptodate.com [Cited 2/3/2022]. Available from:  https://www.uptodate.com/contents/cancer-pain-management-interventional-therapies?source=history_widget#H380437852
• Department for Transport. Guidance for healthcare professionals on drug driving 2014. [internet] [Cited 2/3/2022]. Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/325275/healthcare-profs-drug-driving.pdf
• Gomes T, Juurlink DN, Antoniou T, Mamdani MM, Paterson JM, van den Brink W. Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study. PLoS Medicine. 2017;14(10):e1002396.
• NICE clinical guideline [CG 173]. Neuropathic pain in adults: pharmacological management in non-specialist settings. [Cited 1/3/2022]. Available at:
  https://www.nice.org.uk/guidance/CG173/chapter/1-Recommendations#treatment
• Greater Manchester Medicines Management Group. Neuropathic pain in adults-guideline for primary care 2019 [Internet] [Cited 1/3/2022]. Available at: https://gmmmg.nhs.uk/wp-content/uploads/2021/08/GMMMG-Neuropathic-Pain-Guidance-approved-by-PaGDSG.pdf