Non-opioid ± adjuvant

Paracetamol

• is most commonly used and may be given orally, intravenously and rectally.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDS)

NSAIDs have a valuable role in palliative care for many pains. Consider NSAIDs for bone pain, liver pain, soft tissue infiltration, and inflammatory pain.

Use NSAIDs with caution if a history of peptic ulceration, cardiovascular and renal impairment, clotting difficulties or asthma. It is generally advisable to consider using a PPI if risk of GI side effects.

Ibuprofen

• has the safest GI profile but is the weakest analgesic.

Naproxen

• is a stronger analgesic but it has a higher incidence of side-effects compared to ibuprofen.

Other NSAIDs may be considered if the above choices are ineffective.

Please refer to section 10.1.1 for further information on NSAID prescribing.

Weak opioid for mild to moderate pain ± non-opioid, ± adjuvant, ± anti-emetic and laxative

Tramadol and buprenorphine are rarely used in palliative medicine, but patients may present to your care on them. If this is the case, continue and, in the event that they need to be altered – seek advice.

Codeine phosphate

• Maximum daily dose = 240mg
• Total daily dose of 240mg codeine has approximately equivalent analgesic effect to 20mg-30mg oral morphine per 24 hours

Co-codamol 30/500mg

• Maximum daily dose = 8 tablets/capsules (240mg/4g)
• Total daily dose of 240mg codeine has approximately equivalent analgesic effect to 20mg-30mg oral morphine per 24 hours*

Tramadol

• Maximum daily dose = 400mg
• Total daily dose of 400mg tramadol has approximately equivalent analgesic effect to 40mg oral morphine per 24 hours* see section 4.7.2 Opioid analgesics

*Note: conversions are approximate and vary between individuals

Stop any step 2 opioid. If step 2 is omitted the starting dose of strong opioids should be lower and titrated upwards as necessary.

Strong opioid ± non-opioid, ± adjuvant, ± anti-emetic and laxative

Please refer to NICE Clinical Guideline 140: Opioids in palliative care: safe and effective prescribing of strong opioids for pain in palliative care of adults (May 2012)

Seek advice from the palliative care team if the pain is severe and not responding to treatment, or if the patient reports episodes of acute severe pain unresponsive to breakthrough analgesia or if the pain is worse on movement.

Seek specialist advice before prescribing strong opioids for patients with moderate to severe renal or hepatic impairment.

Starting and Titrating:

• When starting treatment with strong opioids, offer patients with advanced and progressive disease regular oral sustained-release or oral immediate-release morphine (depending on patient preference), with rescue doses of oral immediate-release morphine for breakthrough pain
• Do not routinely offer transdermal patch formulations as first-line maintenance treatment to patients in whom oral opioids are suitable
• Adjust doses to achieve balance between pain control and side effects
• If more than a few adjustments are needed – seek specialist advice [link]
• Offer frequent review during titration

If oral opioids not suitable:

• Only use fentanyl patches for stable patients with stable pain
• Morphine sulfate is the first line SC opioid and appropriate for unstable pain
• Pethidine has no place in patients with advanced illness

Prescribe regular laxative for all patients and consider when required or regular anti-emetics. Nausea is often self-limiting.

Drowsiness may occur at initiation and following an increase or after a when required dose but is usually self-limiting.

Psychological dependence and opioid tolerance are very rare in patients with advanced illness.

Use lower doses and increase analgesia more slowly if individual is frail, elderly or has renal impairment.

Immediate release morphine

Use immediate release morphine (tablet or oral solution) 2.5-10mg four hourly depending on pain severity, general condition and previous use of weak opioids.

Increase four-hourly dose if pain not controlled - suggested increments are:

• 5mg →10mg → 15mg → 20mg → 30mg → 40mg → 60mg → 90mg

Once the daily opioid requirement is established with stable doses over at least 24 hours conversion to a slow release preparation can occur. Add up the total daily dose of opioid used and divide by 2 for a twice daily long acting regime.

Modified-release 12 hourly morphine (Zomorph)

To start an individual using modified release, use regular Zomorph, prescribe 10-15mg 12 hourly.

Breakthrough pain

• Prescribe immediate release oral morphine at 1/6th 24 hourly morphine dose as required
• Assess 30-60 minutes after breakthrough dose
• If pain persists – give a second breakthrough dose
• If pain still not controlled – seek advice
• Some types of movement-related or episodic breakthrough pain are best controlled with a very short acting opioid – seek advice
• If multiple breakthrough doses required, consider increasing regular medication. Increase 12 hourly oral morphine doses in steps of about 30% (or according to breakthrough doses) until pain controlled or side effects develop
• If pain not controlled and developing side effects – seek advice

Records of administered breakthrough pain doses are essential to allow for the effective assessment of pain control and timely adjustments to the continuous analgesic dose.

Other oral preparations

Oxycodone

• Available as both immediate and sustained release preparations, with high oral bioavailability. See section 4.7.2 Opioid analgesics for preparations.
• May be used in individuals with renal failure
• 1mg oral morphine = 0.5mg oral oxycodone (2:1 conversion ratio)
• Prescribe oral preparations by brand. Oral oxycodone modified release preparations are available in 12-hourly and 24-hourly (non-formulary) formulations. Oral oxycodone immediate release preparations are available as capsules and tablets (non-formulary) formulations. Brand-name prescribing is recommended to reduce the risk of confusion and error in dispensing and administration. Formulary options:
  • Shortec immediate release capsules
  • Longtec modified release tablets (12 hourly dosing)

Methadone

• To be used only under specialist advice only
• Methadone has substantial structural differences to morphine but can have generally similar effects, and may help in patients poorly responsive to morphine. Because of a long but variable half-life making individual dose titration difficult, expert advice is needed before using methadone

Where individuals are able to take regular oral opioid medication, and there is thought to be no problem with absorption, there is no theoretical benefit (i.e. no greater potency or efficacy) in administering opioids parentally.

For all opioids administered by continuous subcutaneous infusion:

• After conversion the dose must be titrated against symptom relief
• When first setting up a syringe driver, it may be beneficial to give a SC bolus dose of morphine sulfate or appropriate opioid equivalent to one sixth (1/6) of the 24 hourly doses. (It takes approximately 4 hours to reach a steady plasma level if a bolus dose is not given)
• Consider the need for reduction in SC dose compared to baseline oral doses, especially where there has been poor oral absorption e.g. vomiting or bowel obstruction
• Allow time for infusion to reach therapeutic level before changing doses. In practice this is at least 6 hours. Use when required medication to cover in the mean-time

Morphine

• Morphine sulfate injection is the first line SC opioid and appropriate for unstable pain
• 1mg oral morphine = 0.5mg SC morphine (2:1 conversion ratio)

For opioid naïve patients without immediate pain

• Prescribe morphine sulfate 2.5mg - 5mg SC as required
• Review after 24 hours. If the individual requires 3 or more doses consider starting a syringe driver

For opioid naïve patients in pain

• Prescribe morphine sulfate 10mg - 15mg over 24 hours via SC syringe driver (continuous subcutaneous infusion)
• The dose is dependent on weight, age, renal function and general frailty

and

• Prescribe morphine sulfate 2.5mg - 5mg SC or one sixth (1/6 ) of total24 hours morphine sulfate SC dose for breakthrough pain as required
• Review after 24 hours. If the individual requires 2 or more doses consider increasing dose in syringe driver

In patients already on oral morphine

1mg oral morphine = 0.5mg SC morphine (2:1 conversion ratio)

• Total 24 hr SC morphine sulfate dose as a continuous infusion = Total24 hr oral morphine dose divided by 2
  • e.g. for a patient taking morphine sulfate M/R 60mg 12 hourly
    • 120mg (oral morphine/day) divided by 2 = 60mg SC morphine/day

If the pain has been poorly controlled before the switch to a syringe driver, it may be necessary to calculate the baseline dose of morphine sulfate as above, but then increase the syringe driver content by 20% to improve pain control.

It may also be necessary to give when required SC doses to alleviate pain until the syringe driver has had time to work effectively (approximately 4 hours).

If after 6-12 hours, pain is still poorly controlled, then a dose increment of 20% in the syringe driver should be considered.

Depending on clinical circumstances, the dose increments may need to be lower or higher than the suggestion of 20%.

If the volume of medications in the syringe driver is a concern, advice should be sought from the specialist palliative care team. Do not start new patients on diamorphine 5mg or 10mg injection as supplies will be unpredictable in the future (DHSC, March 2020).

Breakthrough pain

Patients receiving continuous analgesia infusions may still experience acute episodes of pain. These often occur in response to movement or dressing changes etc. It is essential that patients are able to receive additional doses of analgesia to treat this breakthrough pain.

A separate bolus subcutaneous morphine sulfate dose should be prescribed for use as required.

Morphine sulfate SC dose for breakthrough pain = 24 hour morphine sulfate SC dose divided by 6

If 24 hour infusion dose is increased the 'breakthrough' dose will also need to be recalculated.

Records of administered breakthrough pain doses are essential to allow for the effective assessment of pain control and timely adjustments to the continuous analgesic dose

Buprenorphine patches are rarely used in palliative medicine, but some patients may already be on these. If this is the case, continue them and, in the event that they need to be altered – seek advice.

Remember to check for patches in the unwell palliative patient – they may forget to mention these in their tablet list.

Oral morphine to fentanyl patch 150:1 conversion ratio

• 90mg oral morphine/24 hours = 25 microgram/hour fentanyl patch
  • e.g. 90mg oral morphine/24 hours = 3.75mg/hour oral morphine

3.75mg/hour oral morphine = 0.025mg/hour fentanyl patch = 25micrograms/hour fentanyl patch

Fentanyl (Opiodur)

Indications for fentanyl patches:

• Must have stable, controlled pain
• Swallowing difficulties
• Alternative opioid route for some individuals with nausea and vomiting
• Concordance issues
• Chronic renal failure
• Consider for some difficult, opioid induced constipation

Notes

1. Fentanyl patches should not be used for titration or acute pain.
2. Use immediate release morphine for breakthrough pain or withdrawal symptoms – this should be prescribed for when required use in anticipation of need.
3. Patches should be replaced and sited in a different place on the body every 72 hours.
4. Fentanyl is less constipating than morphine. Halve the dose of laxatives when starting fentanyl and then re-titrate.
5. Absorption may be increased if the patient is pyrexial, leading to possible toxicity problems – the patient will need more careful monitoring in this situation.
6. All patients should be advised to avoid exposing the fentanyl transdermal patch application site to direct external heat sources such as heating pads, electric blankets, hot water bottles and prolonged hot baths.

Refer to prescribing notes in section 4.7.2 Opioid analgesics for further prescribing notes and MHRA Drug Safety Updates.

When converting from modified release oral morphine to a fentanyl patch

The first fentanyl patch needs to be applied at the same time as the last 12 hourly modified release dose of morphine.

When converting from immediate release oral morphine to a fentanyl patch

Patients will usually require 3 x 4 hourly doses until the subcutaneous depot has built up i.e. continue immediate release morphine for 6-12 hours.

Patients who will occasionally need to be converted from a fentanyl patch to an alternative opioid. Such switches can be complex given the long half-life of the drug when it is delivered by a patch. In such cases consult Palliative Care Team for advice.

For patients in the last few days of life on a fentanyl patch

Continue patch and change every 72 hours as before.

If pain occurs, give breakthrough doses of oral/SC opioid. The breakthrough dose should be approximately one sixth (1/6) of the total opioid dose. When calculating doses refer to the guide to equivalent doses for opioid drugs here or contact the specialist palliative care team.

If 2 or more breakthrough doses are needed in 24 hours, consider starting an opioid syringe driver and continue the current dose of fentanyl patch. The starting dose of opioid in the syringe driver should be calculated using the total breakthrough doses given in the previous 24 hours.

E.g. if patient is on fentanyl 25mcg/hr patch, and has received 2 doses of morphine sulfate 10mg oral, then you may decide to start morphine sulfate injection 10mg/24hr via SC syringe driver.

Once patient is on fentanyl patch and opioid via syringe driver

Step 1: Calculate new breakthrough dose of 'as required' opioid

1. Calculate the dose of opioid injection over 24 hr equivalent to the fentanyl patch strength
2. Add this to the dose currently given by syringe driver over 24 hr
3. Divide this total by 6 to calculate an approximate new breakthrough dose of injectable opioid to be given SC as required

E.g. using example above: fentanyl 25mcg/hr patch is equivalent to 30 - 45mg/24hr morphine sulfate injection. Syringe driver is delivering an additional 10mg/24hr, hence total regular dose received by patient is 40 - 55mg SC in 24hr. Based on that, an appropriate breakthrough dose might be morphine sulfate injection 7.5mg SC as required.

Step 2: Calculating an increase in opioid dose via syringe driver

1. During subsequent days, review the nature of breakthrough doses used. Decide whether an increase in reqular opioid is indicated.
2. If indicated, then consider adding the sum of breakthrough doses given in previous 24 hr to the dose currently given by syringe driver over 24 hr.
3. Alternatively, if pain is poorly controlled, you may consider a larger increase, e.g. by up to 33% of the patient's total regular opioid dose.
4. Each time the dose via syringe driver changes, recalculate the new breakthrough dose as in Step 1.

E.g. continuing example above:

• Patient is on fentanyl patch 25mcg/hr and morphine sulfate injection 10mg/24hr.
• In the previous 24hr, they have received 2 doses of morphine sulfate injection 7.5mg SC for breakthrough pain.
• Based on this, you may add the sum of breakthrough doses (2 x 7.5mg = 15mg) to the 24 hr dose given by the syringe driver (10mg) resulting in a new dose of 25mg/24hr via syringe driver
• Alternatively, based on the total regular opioid dose (i.e. fentanyl patch plus morphine via syringe driver) being equivalent to morphine sulfate injection 40 - 55mg/24hr, one-third of this is approximately 15mg too. Hence using this method, the new syringe driver dose would also increase from 10mg to 25mg/24hr.
• The new breakthrough dose would be one-sixth (1/6) of 55 - 70mg, hence approximately morphine sulfate 10mg SC as required

If you are in any doubt about these calculations, ask for specialist advice

If symptoms persist contact the local specialist palliative care team

The conversions quoted are approximate and vary between individuals. Conversion ratios are never more than an approximate guide.

Caution is always necessary because of wide inter-individual variation in opioid pharmacokinetics and other variables such as nutritional status and concurrent medication.

At higher doses these variations require the consideration of a reduction in the dose when converting from one strong opioid to another as there is a risk of sedative side effects.

Careful monitoring during conversion is necessary to avoid both under dosing and excessive dosing.

Drug conversions can be challenging and it is often helpful to double check them with a colleague.

If in any doubt seek specialist palliative care advice.

A guide to equivalent doses of opioids used in palliative care has been developed by local specialists across the region. Please note this is not a definitive set of equivalences. The guide is hosted on the Rowcroft Hospice website and can be accessed here.

Please be aware that supplies of diamorphine 5mg and 10mg injection will be unpredictable for the foreseeable future (DHSC, March 2020). For patients requiring subcutaneous pain relief, morphine sulfate injection is the first line opioid if clinically appropriate. If volume of medications in the syringe driver is a concern, advice should be sought from the specialist palliative care team

Do not start new patients on diamorphine 5mg and 10mg injection, and review patients currently receiving these injections. See section 4.7.2 Opioid analgesics for a list of preparations

There are two main types of breakthrough pain:

• Predictable (incident) pain, related to movement (the majority) or activity, e.g. swallowing, defaecation and coughing. It may also occur in response to dressing changes.
• Unpredictable (spontaneous) pain, unrelated to movement or activity.

Two important first steps in managing breakthrough pain are to optimise the “around the clock" analgesia (background analgesia), and to avoid or manage the precipitating factors.

It is essential that patients are able to receive additional doses of analgesia to treat this breakthrough pain.

If background analgesia doses change remember to change breakthrough doses.

Records of administered breakthrough pain doses are essential to allow for the effective assessment of pain control and timely adjustments to the continuous analgesic dose.

Treatment for breakthrough pain is often satisfactory with immediate release oral morphine. When more rapid onset and briefer duration of action are of significant clinical importance the greater cost of sub-lingual fentanyl citrate may be justified.

Morphine (oral solution or tablets)

• Approximate time to onset: 20 – 30 minutes
• Duration of action: 4 hours

Oxycodone

• Approximate time to onset: 20 – 30 minutes
• Duration of action: 4 - 6 hours
• Prescribe oral preparations by brand.Oral oxycodone immediate release preparations are available as capsules and tablets (non-formulary) formulations. Brand-name prescribing is recommended to reduce the risk of confusion and error in dispensing and administration. Formulary immediate release options:
  • Shortec immediate release capsules 5mg, 10mg, 20mg
  • Shortec oral solution sugar free 5mg/5ml

Abstral (fentanyl SL tablet)

• May be used for individuals in renal failure (eGFR <30), only under specialist advice from Renal Team or Specialist Palliative Care
• Requires dose titration to determine optimal dosage
• Approximate time to onset: 10 minutes
• Effective at one hour post dose

True opioid intolerance is very rare.

Opioids will often cause adverse effects which can usually be treated successfully:

• Nausea may settle in 2-3 days but in some patients long-term anti-emetics are needed
• Drowsiness will usually settle in 2-3 days. Explanation and reassurance are crucial
• Constipation will occur in almost all patients. All patients prescribed an opioid should be co-prescribed a laxative (see section 1.6 Laxatives)

Opioid toxicity syndromes

Rarely a patient has an idiosyncratic adverse effect which necessitates a reduction in dose or change to an alternative opioid (see below).

Opioid induced cognitive failure produces psychomotor disturbance, cognitive impairment, drowsiness or hallucinations.

Opioid induced hyperexcitability produces myoclonus, hyperalgesia and allodynia. Both syndromes are important to recognise and respond to by reducing the dose of opioid or by a change of opioid.

Opioid overdose features include drowsiness and respiratory depression. Patients nearing the end of their life are also drowsy and experience breathing changes (e.g. Cheyne-Stokes breathing) due to the advanced stage of their illness. This makes differential-diagnosis difficult at this time. In this setting the incidence of life threatening respiratory depression due to opioids is extremely rare.

Particular caution is needed with fentanyl patches due to their long duration of action even once the patch is removed.

Naloxone is very rarely required in palliative care patients. The use of naloxone at the end of life can cause a pain crisis resulting in poor symptom control and agitation for the patient and extreme distress to their family witnessing this. This significant burden needs to be factored into any treatment decision in this setting.

If, following assessment, professionals are uncertain whether the patient is nearing the end of their life; consider seeking advice from the specialist palliative care team. If the patient is thought to be dying, staff should provide appropriate end of life care.

If toxicity syndromes occur or if rapid escalation of doses of morphine fails to produce analgesic effect, an alternative strong opioid can be used. Fentanyl or oxycodone are logical alternatives to morphine, although methadone is most helpful in hyperexcitability syndromes.

Expert advice should be sought about possible opioid toxicity and its best management.

In addition to an excessive opioid dose due to over-infusion or an excessive bolus dose, the commonest reasons for development of opioid toxicity in the palliative setting are:

• Development of renal failure in a patient on a renally excreted opioid (e.g. morphine or diamorphine) – consider checking renal function
• Reduction of pain relative to opioid dose following a procedure such as radiotherapy or successful nerve block

Seek specialist advice when managing palliative patients with renal impairment.

If eGFR is less than 30mL/minute/1.73m² use renal end of life care plan for opioid use.

NSAIDs should not usually be prescribed in renally impaired patients unless on the recommendation of a specialist.

Close monitoring of renally impaired patient is required whichever opioid is used.

Accumulation of opioid of active metabolites may lead to a prolonged duration of action and increased toxicity.

When possible in renally impaired patients, optimize the use of adjuvant analgesia before introducing an opioid.

If opioids are required:

• Start at lower than usual doses
• Consider increasing intervals between doses
• Monitor closely for toxicity – immediate and delayed

Fentanyl

• SC fentanyl may be used for individuals in renal failure (eGFR less than 30), only under specialist advice
• 30mg oral morphine = 200 micrograms SC fentanyl (150:1 conversion ratio)

Alfentanil

• SC alfentanil may be used for individuals in renal failure (eGFR <30), only under specialist advice
• 30mg oral morphine = 1mg SC alfentanil (30:1 conversion ratio)

Oxycodone

• Available as both immediate and sustained release preparations, with high oral bioavailability.
• May be used in individuals with renal failure
• 1mg oral morphine = 0.5mg oral oxycodone (2:1 conversion ratio)
• Prescribe oral preparations by brand. Oral oxycodone modified release preparations are available in 12-hourly and 24-hourly (non-formulary) formulations. Oral oxycodone immediate release preparations are available as capsules and tablets (non-formulary) formulations. Brand-name prescribing is recommended to reduce the risk of confusion and error in dispensing and administration. Formulary options:
  • Shortec immediate release capsules and oral solution sugar free 5mg/5ml
  • Longtec modified release tablets (12 hourly dosing)

All principles of pain management apply for the use of adjuvant analgesics.

Ensure the first line adjuvant analgesic is at its pharmacologically effective dose level and interval before changing to/adding second line drugs.

Many of the drugs classified as adjuvant analgesics were developed and released for clinical indications other than pain.

If progressive pain control is not being achieved – seek advice

Please refer to Neuropathic pain

Corticosteroids

Used for the treatment of neuropathic pain caused by infiltrating cancers. They are particularly important when neuropathic pain is associated with limb weakness.

Dexamethasone

• Give before mid-afternoon – preferably once daily as a morning dose
• Use lowest effective dose for indication
• Give as a trial for 5 days and stop if no improvement

Common indications and doses:

• Raised intracranial pressure: 8-16mg/day
• Nerve pain and cord compression (important if associated with limb weakness): 8-16mg/day
• Liver pain: 4-8mg/day

Adverse effects:

• These are many, but important ones of relatively rapid onset are:
• Diabetes mellitus
• Paranoid psychosis
• Wasting
• Agitation or depression
• Peptic ulceration
• Skin damage
• Insomnia
• Weakness in proximal muscles