7th January 2024

Strong opioids

Strong opioids are step 3 of the WHO analgesic ladder. As discussed above, it is common for step 2 to be bypassed. When a strong opioid is prescribed, the weak opioid must be stopped. Opioids generally are effective across different pain types.

There are a number of options for strong opioids. Most commonly encountered in MRCP part 1 are Morphine, Oxycodone, and Fentanyl. There can be specific indications for choosing one drug over another. However, there is significant overlap between their properties. Not only are different drugs available, but there is good flexibility in routes of administration to give utility in a number of scenarios.

Studies have not shown superiority of morphine over other opioids. However, morphine is the mainstay of analgesic guidelines due to familiarity and availability. There are also cost considerations.

Mechanism of action

The three best-known opiate receptors are mu, kappa, and delta. The most clinically significant is the mu receptor. Most opioid metabolites act as agonists at this receptor. Receptor antagonists such as Naloxone are used in reversal of opioid side effects.

Nociceptive pain increases the number of opiate receptors peripherally. Opioids act upon these receptors peripherally to give analgesia.

Dosing

Starting on strong opioids can be with either immediate release or modified release preparations. Immediate release strategies are given as required for breakthrough pain, whereas modified release attempts to control patient’s pain over a 24-hour period. NICE recommends starting doses of:

• 5mg of oral morphine 4 hourly for immediate release strategy. or

• 15mg modified release morphine twice daily, plus 5mg immediate release as required for breakthrough pain.

The above demonstrates that even with a modified release strategy, it is important to co-prescribe an immediate release preparation. Typical teaching is that a breakthrough dose should be between 1/6 and 1/10th of the regular dose, with a maximum of 4 hourly. Taking a history will establish the dose that works for each individual patient – which could be higher or lower, and can be a guide.

Titration

Dose titration depends on the control of the patient’s pain and the medications they have required. Starting modified release preparation following an immediate-release strategy depends on the doses of immediate-release which have been required to control the pain. If a patient has taken four 5mg doses of immediate-release morphine in 24 hours:

• 4 x 5mg = 20mg daily morphine dose ÷ 2 = 10mg modified release twice a day
• 20mg morphine daily dose ÷ 6 = 3.3mg breakthrough dose

3.3mg is a difficult dose to draw up and give. Normally, morphine is given in measures of 1.25mg, so 2.5mg would be a good as required dose in this example.

Where modified release preparations have already been chosen but have been ineffective, dose increases will be based on breakthrough requirements. However, dose increases are usually kept at between 33-50% per day to avoid complications from rapid titration. Where the modified release dose is uptitrated, the breakthrough dose should also be increased if it is ineffective or not reaching the 1/6 – 1/10ᵗʰ thresholds.

Incident pain

Some pains are related to predictable events. Periods of expected activity, such as shopping, may be associated with pain at home. In the healthcare setting, patients may find receiving personal care painful. This is referred to as ‘incident pain.’ This may be controlled with lifestyle modifications, but immediate-release opioids are also useful for patients who can use this in anticipation of an incident. Increasing the background dose of opioids may not prevent episodes of incident pain, and the use of immediate-release opioids for these pains should not necessarily be used as a guide to increase background dose.

Routes and dose conversion

As mentioned before, there are a number of strong opioids available. Not all drugs are equal. Although some drugs are ‘stronger’ than others, dose titration is a more appropriate method to achieve pain control than switching opioids initially. Opioid rotation is an option where pain is continually not controlled with one drug despite uptitration but would be guided by a specialist. Switching between two different drugs happens frequently in palliative care due to changes in a patient’s condition, such as the development of renal failure. Where patients are already established on analgesia, converting the dose accurately avoids the development of side effects and loss of pain control.

Source: https://gmmmg.nhs.uk/guidance/clinical-guidance-and-pathways/

Converting from one drug to another is possible using the table above for reference. The key steps are:

• Calculating the total opioid dose (maintenance and breakthrough)
• Converting to oral morphine
• Convert to final opioid

Most conversion tables available for various opioids will quote the conversion to or from oral morphine. It is, therefore, safer, simpler, and more accurate to convert between the drug in question and oral morphine before converting to the opioid of choice.

For instance, if a patient takes 240mg of codeine a day, and the equivalent dose of oxycodone was required:

• 240mg ÷ 10 = 24mg equivalent dose of morphine
• 24mg ÷ 2 = 12mg equivalent dose of oxycodone

Even within the same drug, the relative strength varies across different routes. This has implications in clinical practice. Oral is the preferred route for analgesia, but where this is not available (nausea and vomiting, tablet burden, poor absorption, reduced consciousness), alternatives need to be considered, and conversion may be required.

Transdermal route

The transdermal route is an option where the oral route is not available. This involves the application of patches, most commonly fentanyl or buprenorphine. These patches remain in place for days at a time, the duration different between different brands. The absorption of patches can be increased by heat, for instance, in pyrexia, and can cause side effects and toxicity.

Patches reach a steady state over a period of days. They are typically used in stable, well-controlled pain and are not appropriate for unstable pain. However, if pain becomes unstable, abruptly stopping the patch would not be appropriate. Other opioids can be added alongside the patch in that case.

Both fentanyl and buprenorphine patches are only available in certain doses with less flexibility than oral alternatives. Conversion is not as straightforward as a simple equation. This again demonstrates the utility of morphine as a ‘currency’ for opioid conversions because of the widespread availability of conversion information. There may not be an exact equivalent patch compared to the existing dose of opioid, and a slight dose reduction is preferable.

Source: https://gmmmg.nhs.uk/guidance/clinical-guidance-and-pathways/

As you can see, even the lowest-strength fentanyl patch is a comparatively large opioid dose. It is, therefore, recommended not to use fentanyl in opioid naïve patients.

Using the table above to switch from 120mg daily oral oxycodone to a fentanyl patch:

• 120mg ÷ 2 = 60mg equivalent dose of oral morphine
• 60mg = Fentanyl 25mcg/hour patch

When switching between modified release agents and transdermal, the patch should be applied at the same time as the final modified release preparation is taken.

Subcutaneous route

Subcutaneous syringe drivers are widely used in palliative care to deliver a range of medications, not just analgesics. Syringe drivers are dosed over 24 hours – with the prescribed drug being put into an infusion over 24 hours. This provides a constant supply of drugs without peaks and troughs. They are commonly used at the end of life. As required, doses can also be made available subcutaneously. There is no ‘immediate-release’ or ‘modified-release’ version of the injection, and it is the same drug either administered as a bolus or over 24 hours. There are often direct oral to subcutaneous conversion equations available within the same drug (such as oxycodone), so conversion to oral morphine is not always necessary.

Syringe drivers should be commenced immediately if the patient is not receiving opioids or is only taking immediate-release oral opioids. If the patient takes modified-release opioids, the syringe driver should be commenced at the time the next modified-release preparation is due.

Source: https://gmmmg.nhs.uk/guidance/clinical-guidance-and-pathways/

Cautions

Renal impairment

There is little evidence for opioid choice in renal impairment. Practice is mainly guided by clinical experience, but there are some important considerations with certain drugs:

• Morphine metabolites are renally excreted. Renal impairment can, therefore, increase the half-life and cause accumulation and an increased side effect burden. At an eGFR of 20-50ml/min, it is used at 75% of the normal dose. Below that, alternative opioids are recommended.
• Oxycodone is preferred in renal impairment to morphine in some hospital trusts, but there is still the risk of accumulation. Modified-release oxycodone should be avoided in stage 4-5 CKD, but immediate release can be used.
• Alfentanil is safe in renal failure and is the drug of choice in stage 4 & 5 CKD if a syringe driver is needed. There is also a sublingual option.

Across all drugs, the dose should be slowly and carefully titrated, as rapid changes can cause accumulation.

Hepatic impairment

Unlike renal impairment, there is no figure by which to grade hepatic impairment, meaning there are no cut-offs for dose changes. Most opioids are metabolised in the liver, so there is an increased risk of toxicity. Drugs should be started at lower doses and titrations slower as a result. With regard to specific drugs:

• Oral morphine bioavailability can be increased to 100% in hepatic impairment. It can be used safely with cautious use but should be avoided if there is both liver and kidney failure, e.g., hepato-renal syndrome.
• Oxycodone effectiveness and onset can be impacted, as can clearance. It should be avoided in moderate to severe hepatic impairment.
• Fentanyl is metabolised to non-active metabolites, so can be safely used in hepatic failure. It is particularly useful where there is both hepatic and renal failure.

Driving

Driving rules are a favourite question in the exam. Taking strong opioids is not a reason to stop driving or inform the DVLA. Although drug driving is an offence, a medical defence can be raised where the drug is legally prescribed and taken in accordance with the advice of the prescriber. Patients who do not follow this advice may be liable to prosecution. It is therefore important to be aware of and alert patients to the following rules:

• Patients should carry evidence of their legal prescription for the drug.
• Drivers should not drive if they are impaired by the drug. To drive if they are drowsy, for instance, is an offence.
• Patients should be advised not to drive when starting or titrating the dose of opioids, as this increases the risk of sedation.

Side effects

Strong and weak opioids cause many side effects. The most important things to be aware of for the exam are discussed here, but this is by no means an exhaustive list.

Constipation

Constipation is a significant side effect, affecting 60% of patients taking opioids. It is the most frequently reported side effect. NICE guidelines recommend commencing laxatives alongside opioids: senna is recommended as a first choice, at 15mg at night with dose titration and addition of other agents based on response.

Mu receptors in the GI nervous system are bound by opioids, causing slowed GI transit, increased water reabsorption, and constipation. This may lead to cramping abdominal pain from an increase in non-propulsive contractions.

Nausea

Opioid-induced nausea is less common than constipation but is still a side effect to recognise and manage. Nausea is a common transient side effect shortly after commencing opioids. Delayed gastric emptying and direct effects on the chemoreceptor trigger zone are two mechanisms where symptoms continue long-term.

Antiemetic therapy, in this case, depends on history:

• In the context of associated bowel dysfunction, constipation should be well managed. A prokinetic antiemetic such as metoclopramide 10mg three times a day would be the first choice.
• If there were no bowel symptoms, a centrally-acting antiemetic such as haloperidol is preferred. Ondansetron could be an option, but this is frequently constipating, so may worsen symptoms.

Respiratory depression

This is a life-threatening, easily reversible emergency. Risk factors for developing respiratory depression include rapid increase in opioid dose, deterioration in renal function, and co-prescription of benzodiazepines and gabapentinoids. Rapid treatment with Naloxone is required to reverse the effect of the opioid.

Naloxone administration can cause a severe acute withdrawal syndrome and pain. The dose must be carefully titrated against the respiratory rate:

• Where the respiratory rate is >8, monitor only. Reduce or remove any opioids.
• Where the respiratory rate is <8, and the patient is arousable, give 100 micrograms IV Naloxone every 2 minutes until respiratory rate >8.
• Where there is no respiratory effort, 400 micrograms IV Naloxone should be given, followed by 800 micrograms after 1 minute if no response.

References

• Twycross R, Wilcock A, Howard P. Palliative Care Formulary 6ᵗʰ edition 2017. 260-467
• Scottish Palliative Care Guidelines [Internet]. 2020 [Cited 28/2/2022]. Available at: https://www.palliativecareguidelines.scot.nhs.uk/
• NICE clinical guideline [CG140]. Palliative care for adults: strong opioids for pain relief. [Cited 28/2/2022]. Available at:
  https://www.nice.org.uk/guidance/cg140/chapter/1-Recommendations
• Greater Manchester and Eastern Cheshire Strategic Clinical Networks. Palliative Care Pain & Symptom Control Guidelines for Adults 2019 [Internet] [Cited 28/2/2022]. Available at: https://gmmmg.nhs.uk/guidance/clinical-guidance-and-pathways/
• UpToDate [Internet]. Uptodate.com [Cited 28/2/2022]. Available from:
  https://www.uptodate.com/contents/cancer-pain-management-with-opioids-optimizing-analgesia?search=cancer%20pain%20management&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H27
• UpToDate [Internet]. Uptodate.com [Cited 28/2/2022]. Available from:
  https://www.uptodate.com/contents/prevention-and-management-of-side-effects-in-patients-receiving-opioids-for-chronic-pain?search=opioid%20side%20effects&source=search_result&selectedTitle=3~143&usage_type=default&display_rank=1#H3871239225
• Müller-Lissner S, Bassotti G, Coffin B, et al. Opioid-Induced Constipation and Bowel Dysfunction: A Clinical Guideline. Pain Medicine. 2017;18(10):1837-1863.
• Dean M. Opioids in renal failure and dialysis patients. Journal of Pain and Symptom Management. 2004;28(5):497-504.