• Prescribe analgesia for continuous pain on a regular basis, in addition to as-required analgesia.
• Consider a stepwise approach, using the World Health Organization analgesic ladder. Start at the appropriate point of the analgesic ladder, moving up the ladder when the maximum dose at each step is reached until the person is comfortable. The steps are:
• Non-opioid analgesic: paracetamol and/or nonsteroidal anti-inflammatory drug (mild pain).
• Weak opioid, with or without a non-opioid analgesic (mild-to-moderate pain).
• Strong opioid, with or without a non-opioid analgesic (severe pain).
• At any stage, consider the addition of a non-opioid adjuvant drug.
• Review regularly (consider a telephone call if appropriate), step treatment up or down as necessary, and stop unnecessary medication that has not worked.

In depth

• Paracetamol and/or a nonsteroidal anti-inflammatory drug (NSAID) are recommended first line.
• If an NSAID is appropriate and not contraindicated:
• Ibuprofen, diclofenac, and naproxen are the NSAIDs of choice.
• The oral route is preferred, but if this is not possible, consider alternative routes (such as rectal).
• Consider prescribing a proton pump inhibitor with an NSAID. For more information on minimizing the risks associated with NSAID treatment, see the CKS topic on NSAIDs - prescribing issues.
• Non-opioid adjuvant drugs may also be useful for some people with specific pain types; see:
• Scenario: Managing colic.
• Scenario: Managing intracranial pressure pain.
• Scenario: Managing muscle spasm pain.
• Scenario: Managing neuropathic pain.
• Scenario: Spinal cord compression.

In depth

• Codeine or dihydrocodeine is recommended:
• If flexibility of dosing and titration of analgesic effect are required, prescribe the weak opioid separately to paracetamol.
• If compliance is likely to be a problem and analgesic requirements are stable, consider prescribing a product combining 500 mg of paracetamol with 30 mg of codeine.
• To prevent constipation, prescribe a stimulant laxative (such as senna or bisacodyl) and a softening laxative (such as docusate).
• A laxative with both properties (for example, co-danthramer or co-danthrusate) is also an option.
• Avoid dantron-containing laxatives in people who are incontinent as these drugs can cause a chemical burn (reddening) of the perianal area.
• Dantron can also colour the urine red and alarm the person.

In depth

• Use the oral route of administration where possible.
• Morphine is recommended:
• For advice on how to initiate morphine and titrate the dose, see Initiating and titrating morphine.
• If the person's compliance with oral morphine is good, but pain is inadequately controlled:
• Review the cause of the pain.
• Consider using a non-opioid adjuvant drug to treat a specific type of pain. See:
• Scenario: Managing colic.
• Scenario: Managing intracranial pressure pain.
• Scenario: Managing muscle spasm pain.
• Scenario: Managing neuropathic pain.
• Scenario: Spinal cord compression.
• If compliance with oral morphine is good, but the person cannot tolerate an adequate dose, consider using an alternative oral opioid — seek specialist advice.
• If the oral route is not appropriate (for example, the person has nausea and vomiting, or cannot swallow, or has poor compliance with oral analgesia), consider:
• Switching to a subcutaneous diamorphine or morphine infusion. For more information, see Switching from morphine to another strong opioid.
• Switching to transdermal fentanyl if the person has stable analgesic requirements and has previously tolerated opioids — seek specialist advice.
• When prescribing a strong opioid:
• Prescribe an anti-emetic (such as metoclopramide for gastric stasis, otherwise low-dose haloperidol):
• If the person has experienced nausea with a previous opioid, give regularly for the first week, to prevent opioid-induced nausea and vomiting and then reassess, or
• If the person experiences nausea with morphine but has not experienced nausea with a previous opioid, prescribe for use on an as-required basis for 1 week.
• To prevent constipation, prescribe a stimulant (such as senna or bisacodyl) and a softening laxative (such as docusate):
• A laxative with both properties (for example, co-danthramer or co-danthrusate) is also an option.
• Avoid dantron-containing laxatives in people who are incontinent as these drugs can cause a chemical burn (reddening) of the perianal area.
• Dantron can also colour the urine red and alarm the person.
• Seek specialist palliative care advice if:
• There is doubt about how to manage a person's pain.
• Adverse effects limit treatment and cannot be adequately managed.
• An unfamiliar opioid or route of administration is being considered.
• The pain is still at 50% or more of its starting level after 2 weeks.

In depth

• Give adequate instructions (written if possible) on how to control breakthrough pain. Inform other healthcare team members, including out-of-hours staff, as appropriate.
• The person should take breakthrough analgesia before the pain gets severe, as it may take 30–60 minutes for the analgesia to reach full effect.
• When deciding whether more than one breakthrough dose is needed, consider the time required for medication to take effect and its potential for adverse effects before administering another dose.
• In a person taking regular analgesia, breakthrough pain indicates a need for reassessment of the analgesic dosage and the underlying cause of pain. For more information on how to increase the dose of oral morphine, see Initiating and titrating morphine.
• If the person is taking regular paracetamol and/or a nonsteroidal anti-inflammatory drug (NSAID), consider:
• Treating with an additional dose of the regular analgesic as long as it does not exceed the maximum licensed dose, or
• Adding in a weak opioid on an as-required or regular basis.
• If the person is taking regular paracetamol and/or an NSAID plus a weak opioid, consider:
• Treating with an additional dose of the regular analgesic as long as it does not exceed the maximum licensed dose, or
• Switching to a strong opioid.
• For people taking oral morphine:
• If the person is using immediate-release or modified-release morphine regularly — treat with immediate-release oral morphine (tablets or liquid), at a dose of one tenth of the total daily oral morphine dose, to be taken when required and repeated no more than 2-hourly.
• The breakthrough dose may need to be individually titrated to between 5% and 20% of the regular daily dose.
• If the person is in severe pain and needs another dose sooner than 2 hourly, seek specialist advice.
• The onset of action of immediate release morphine is about 20–30 minutes; this may not be ideal for those patients with rapid onset severe episodes of breakthrough pain. An immediate-release fentanyl product may be useful in these circumstances. However, immediate-release fentanyl products should only be started by a specialist because:
• There are four immediate release fentanyl products available, all with different routes of absorption: transmucosal lozenges (Actiq^®), sublingual tablets (Abstral^®), buccal tablets (Effentora^®), and intranasal (Instanyl^®).
• These products are not bioequivalent and cannot be substituted for one another.
• The rescue dose needs to be individually titrated — there is no correlation between the regular dose of strong opioid and the effective rescue dose.
• Serious adverse effects and deaths can occur if the products are not used correctly, or if they are used in opioid naive individuals, or for transient pain (such as migraine).
• These products are markedly more expensive than immediate release morphine.
• If the person is receiving a subcutaneous infusion of diamorphine or morphine:
• Treat with a subcutaneous bolus dose at one tenth of the 24-hour infusion dose, when required, and repeated no more than 2-hourly. If the person is in severe pain and needs another dose sooner, seek specialist advice.
• Oramorph^® is an alternative for people who can manage liquids but are on an infusion because they cannot swallow tablets. It allows the person and their family greater control over managing episodes of breakthrough pain without having to wait for a healthcare professional to attend to give a breakthrough subcutaneous dose. Specialist advice should be sought in this situation to check the oral route is appropriate and to clarify the dose of Oramorph^® because the doses suggested by experts vary.
• If using other strong opioid analgesics, seek specialist advice.
• If the person's background pain is satisfactorily controlled but they experience incident pain (pain on movement or particular events, such as micturition, wound dressing, bed care, travel):
• Do not keep increasing the 24-hour dose of opioid.
• Give a breakthrough dose of an immediate-release opioid approximately 30 minutes before the precipitating factor occurs. In some situations, transmucosal fentanyl can be useful for this purpose, but this should be used only on the advice of a specialist.
• Do not include the breakthrough doses administered for incident pain when reassessing maintenance opioid analgesia requirements.

In depth

• Either immediate-release or modified-release formulations are recommended for the initiation of morphine:
• Immediate-release oral morphine has a rapid onset of action (about 20 minutes) that makes it suitable for initiating treatment of severe pain (and for treating breakthrough pain), but it requires administration every 4 hours to maintain a continuous analgesic effect. Consequently, it is difficult to cover pain throughout 24 hours, unless the person is being closely monitored. Immediate-release morphine is useful for titration if the person's pain is severe and rapid titration is required, usually on an inpatient basis. Oramorph^® solution and Sevredol^® tablets are both immediate-release morphine products.
• Modified-release morphine preparations have a slower onset of action (1–2 hours) and later peak levels (4 hours) than immediate-release preparations. Consequently, they cannot be rapidly titrated for people in severe pain. However, in many people, they provide continuous analgesia that is ideal for titration, especially for those at home.
• Take care to avoid prescribing errors:
• Prescribe by mass (for example, 2 mg) rather than by volume (for example, 2 mL).
• Avoid decimal points in doses if possible (for example, 2.5 mg) to minimize the risk of dose errors, and try to avoid prescribing awkward doses.
• If using morphine 10 mg/5 mL solution, doses without a decimal point are easier to measure (for example 2 mg [1 mL of solution]).
• Final doses of morphine cannot be predicted from age, body weight, or body surface area. The starting dose of oral morphine should take into account previous exposure to opioids.
• Starting regimens of oral morphine are listed below as a guide and are based on suggested doses in UK and European guidelines and the Palliative Care Formulary. However, some experts advocate a more cautious approach with lower starting doses. Clinical judgement is therefore required.
• For people not currently taking an opioid:
• In elderly or frail people, start with morphine 2–5 mg every 4 hours plus as required (up to 2-hourly) for breakthrough pain. Cautious dose titration can help to reduce initial drowsiness, confusion, and unsteadiness.
• In young and middle-aged people, start with morphine 5–10 mg every 4 hours plus as required (up to 2-hourly) for breakthrough pain.
• For people previously on a weak opioid (such as codeine) at a full therapeutic dose, start with:
• Immediate-release morphine 10 mg every 4 hours plus as required (up to 2-hourly) for breakthrough pain, or
• Modified-release morphine 20–30 mg every 12 hours plus breakthrough doses of immediate-release morphine as required (up to 2-hourly). For information on calculating the breakthrough dose, see Management of breakthrough pain.
• Consider starting at a lower dose and titrating carefully if the person is elderly or frail.
• For people previously on an alternative strong opioid:
• CKS recommends seeking specialist advice because of the differences in opinion regarding conversion ratios.
• Seek specialist palliative care advice for people with renal impairment, people with increased intracranial pressure, or people at risk of respiratory depression. For people with renal impairment, a lower or less frequent regular dose of morphine may be preferable, or a different opioid may be more appropriate.

In depth

• After 24 hours, recalculate the total morphine requirement: the new 24-hour dose is the total of all the doses given in the previous 24 hours.
• However, care should be taken when calculating morphine requirements for people who are pain-free at rest but have pain on movement. If all the analgesia for this incident pain is incorporated into the new morphine dose, the person is likely to be excessively sedated at rest or possibly opioid toxic. CKS therefore recommends that incident pain doses are excluded when calculating the new 24-hour dose.
• If the person takes two or more as-required doses in 24 hours, increase the regular dose of morphine every 2–3 days (using the as-required amount of morphine used as a guide) until there is adequate pain relief or adverse effects prevent further dose increases:
• Increases of 30–50% have been recommended in the literature. However, expert feedback suggests that it may be safer to limit increases to 30% in primary care to avoid toxicity (especially at higher doses). A report from the National Patient Safety Agency advises ensuring that where a dose increase is intended, the calculated dose is safe for the person (for example, for oral morphine in adults, not normally more than 50% higher than the previous dose).
• Immediate-release morphine:
• If the total 24-hour dose is 90 mg (6 x 10 mg regular doses + 3 x 10 mg as-required doses), the new 4-hourly dose would be 15 mg.
• Once the pain is controlled and a stable 24-hour requirement of morphine is established, the daily dose can be switched to a modified-release preparation in a single daily dose, or in two divided doses.
• Modified-release morphine:
• For a 12-hourly modified-release preparation (Morphgesic^® SR tablets, MST Continus^® tablets or suspension, Zomorph^® capsules), divide the total 24-hour dose of morphine by two. For example, if the total 24-hour dose is 120 mg (2 x 40 mg regular modified-release doses + 4 x 10 mg as-required doses), the new 12-hourly modified-release dose would be 60 mg.
• For a 24-hourly modified-release preparation (MXL^® capsules), the dose is equivalent to the total 24-hour dose of morphine.
• If switching from regular immediate-release to modified-release morphine, give the first dose of modified-release morphine 4 hours after the last dose of immediate-release morphine (and discontinue the immediate-release preparation).
• Because the pharmacokinetic profiles of modified-release products differ, and differences in appearance may be confusing for people, it is best to keep the person on the same brand of modified-release morphine.
• Continue to provide immediate-release morphine tablets or solution for as-required treatment of breakthrough pain.

In depth

Undesirable effects, such as nausea or drowsiness, can occur on starting an opioid or with a dose increase. These may require the use of additional medication, such as anti-emetics, but generally resolve after about 1 week. Occasionally, the dose of opioid may need to temporarily be reduced and titrated up again more slowly. If severe or persistent undesirable effects occur, seek specialist advice, as an alternative opioid may be required.

Oral morphine to another oral strong opioid

• CKS recommends that primary care healthcare professionals seek specialist advice, or consult local guidelines (where available), when selecting the opioid and dose to switch to because experience in primary care is likely to be limited and alternative oral opioids are best initiated by a person with experience in palliative care. Methadone should only be initiated by a specialist because it has a long and unpredictable half-life, with considerable inter-individual variation, and requires careful monitoring.
• There are differences in opinion regarding dose conversion ratios — current practice for converting opioid doses is based on pharmacokinetic drug data (such as bioavailability after oral administration) from observational and uncontrolled studies, and on expert opinion and experience. Reported equi-analgesic dose ratios vary widely among strong opioids. When converting from one opioid to another, regular assessment and reassessment of efficacy and adverse effects is essential because of the lack of evidence on equi-analgesic dose ratios and inter-individual variations. Most specialists would advocate applying the calculation and then allowing a relative dose reduction in case there is incomplete cross-tolerance, which would result in a much greater clinical effect than anticipated.
• Particular attention to monitoring and dose titration up or down is needed when:
• Switching between opioids at high doses.
• There has been a recent rapid escalation of the first opioid.

Oral morphine to subcutaneous diamorphine or morphine

• In primary care, when switching the route of administration of one strong opioid to another, the most common switch is from oral morphine sulphate to subcutaneous diamorphine or morphine.
• Diamorphine is much more soluble than morphine and therefore easier to administer in higher doses. It is also compatible with most other drugs which may need to be administered by a subcutaneous infusion. However, morphine is an alternative, and most people do not require doses large enough to cause solubility issues:
• Parenteral diamorphine is approximately three times as potent as oral morphine, so the total daily dosage of oral morphine should be divided by three to obtain the 24-hour subcutaneous dose of diamorphine. See Table 1.
• The oral to subcutaneous potency ratio of morphine is between 1:2 and 1:3 (that is, the subcutaneous dose is one third to one half of the oral dose). In practice, most centres divide the oral dose by two and re-titrate as necessary. See Table 1.

In depth