Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://emc.medicines.org.uk), or the British National Formulary (BNF) (www.bnf.org).

• For a detailed discussion on the contraindications, adverse effects, monitoring issues, and interactions of nonsteroidal anti-inflammatory drugs, see the CKS topic on NSAIDs - prescribing issues.

• Codeine and dihydrocodeine may cause nausea, vomiting, and drowsiness [BNF 56, 2008].
• Constipation is another common adverse effect [BNF 56, 2008].
• To prevent constipation, prescribe a stimulant laxative (such as senna or bisacodyl) and a softening laxative (such as docusate or lactulose):
• 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.
• For more information, see the CKS topic on Palliative cancer care - constipation.

• 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 [SIGN, 2008]. 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 [McQuay and Moore, 1997; SIGN, 2008]. 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 [Hanks et al, 2001; SIGN, 2008] and the Palliative Care Formulary [Twycross and Wilcock, 2007]. 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).
• 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 [ABPI Medicines Compendium, 2009], or a different opioid may be more appropriate [SIGN, 2008].

• 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 [SIGN, 2008]. 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 [Twycross and Wilcock, 2007]. 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) [NPSA, 2008].
• 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 [SIGN, 2008].
• 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 [BNF 56, 2008].
• 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 [SIGN, 2008]. 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) [BNF 56, 2008].
• 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 [SIGN, 2008].
• Continue to provide immediate-release morphine tablets or solution for as-required treatment of breakthrough pain [Twycross and Wilcock, 2007].

• Exclude any underlying illness or other drugs (such as antipsychotics) that may mimic opioid-induced adverse effects (such as dehydration).
• Drowsiness is common at the start of treatment or after dose increases. Warn people to avoid activities (such as driving) in which drowsiness may be detrimental. Most people develop tolerance to drowsiness within a few days. Persistent sedation can usually be resolved by dose reduction.
• Nausea and vomiting subside after the first few days in many people but can be an ongoing problem for others. An anti-emetic (for example, metoclopramide if the problem is gastric stasis, otherwise low-dose haloperidol) should be prescribed [Twycross and Wilcock, 2007]:
• For more information, see the CKS topic on Palliative cancer care - nausea & vomiting.
• Constipation — tolerance does not develop, but constipation can usually be treated [Twycross and Wilcock, 2007]. 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. Some people taking dantron-containing laxatives may experience a chemical burn (reddening) of the perianal area; these agents are therefore unsuitable for incontinent people. Dantron can also colour the urine red and alarm the person.
• For more information, see the CKS topic on Palliative cancer care - constipation.
• Dry mouth can be troublesome. Consider reducing the dose of, or stopping, any drugs that also cause dry mouth. People should be encouraged to use simple measures first [Fallon and O'Neill, 1997; Doyle et al, 2004; Regnard and Hockley, 2004b; WeMeReC, 2006]:
• Cold, unsweetened drinks.
• Frequent sips or sprays of cold water.
• Ice cubes, crushed ice, or ice lollies.
• Lubricant on the lips.
• Sugar-free products — chewing gum, mints, boiled sweets, or pastilles.
• For more information, and what to do if simple measures are not adequate, see the CKS topic on Palliative cancer care - oral.

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 [BNF 56, 2008]. 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 [SIGN, 2008].
• 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 [Quigley, 2004; SIGN, 2008]. Reported equi-analgesic dose ratios vary widely among strong opioids [Pereira et al, 2001; Mercadante et al, 2005]. 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 [Twycross and Wilcock, 2007]:
• 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.

• For prescribing information, see the section on Tricyclics in the CKS topic on Neuropathic pain - drug treatment.

• For prescribing information, see the section on Pregabalin in the CKS topic on Neuropathic pain - drug treatment.

• For prescribing information, see the section on Gabapentin in the CKS topic on Neuropathic pain - drug treatment.

• Insomnia can occur with dexamethasone use; therefore, the dose is often taken each morning [BNF 56, 2008]. Experts suggest that if the volume of tablets or injection is difficult to manage in a single dose, it is acceptable to split the dose, in which case it should be given at 8 a.m. and 12 p.m. (noon).
• Psychiatric adverse effects include depression and psychosis [BNF 56, 2008]. Other adverse effects include hypertension, hypokalaemia, osteoporosis, worsening of diabetic control, and proximal myopathy [ABPI Medicines Compendium, 2008a].
• Regular mouth care is essential in people taking oral corticosteroids because oral candidiasis is common.
• Consider gastroprotection with a proton pump inhibitor for people at high risk of gastrointestinal adverse effects.
• For people who are immunosuppressed by long-term corticosteroid use, there is a risk of severe chickenpox infection in those who are not immune [DH, 2006]. Advise all such people using corticosteroids to seek urgent medical attention if they come into contact with anyone with chickenpox or shingles [CSM, 1998].
• Dexamethasone may help to improve appetite and a general feeling of well-being.

• The most frequent adverse effects are drowsiness, sedation, muscle weakness, and ataxia. These effects are caused by depression of the central nervous system, and they generally decrease with continued use of the drug [Micromedex, 2007]. Warn the person to avoid activities (such as driving) in which drowsiness may be detrimental.
• Less frequent adverse effects include vertigo, headache, confusion, depression, amnesia, and paradoxical excitation [Sweetman, 2005].

• Sedation and drowsiness are commonly reported adverse effects. Warn the person that drowsiness may affect the performance of skilled tasks (such as driving) and that baclofen may enhance the effects of alcohol.
• The Commission on Human Medicines (formerly Committee on Safety of Medicines) has advised that serious adverse effects (including psychosis, mania, paranoia, convulsions, tachycardia, and hyperthermia) can occur on abrupt withdrawal of baclofen [CSM, 1997]. A gradual reduction over 1–2 weeks is advised, or over a longer period if adverse effects occur during withdrawal.
• Consider using diazepam rather than baclofen in people with:
• Active (or history of) peptic ulceration, as baclofen stimulates gastric acid secretion.
• Psychiatric disorders, such as psychosis, schizophrenia, depression, or mania, as baclofen may exacerbate these conditions.
• Epilepsy, as baclofen may lower the seizure threshold; expert supervision is advised.
• Diabetes, as baclofen may increase blood glucose levels.
• Urinary retention, which may be exacerbated in people with a hypertonic bladder sphincter.
• Renal and hepatic impairment — the initial dose should be reduced in people with moderate-to-severe renal impairment, and titrated upwards according to the response. Liver function should be monitored in people with hepatic impairment.

[Sweetman, 2005; Twycross and Wilcock, 2007; BNF 56, 2008]

• Hyoscine butylbromide should not be administered to people with myasthenia gravis, megacolon, narrow-angle glaucoma, tachycardia, prostatic enlargement with urinary retention, mechanical stenoses in the region of the gastrointestinal tract, or paralytic ileus, as hyoscine may further worsen these conditions.
• Hyoscine butylbromide has a rapid onset of action and starts to take effect within 15 minutes of subcutaneous administration. It has a duration of action of up to 1 hour.
• Common adverse effects of antimuscarinic drugs that may occur with increasing dose include dry mouth, constipation, urinary retention, and blurred vision. CKS found no evidence on the extent to which these occur in people in the terminal phase of illness.
• Hyoscine butylbromide does not readily cross the blood–brain barrier and therefore does not produce central nervous system adverse effects.

[Twycross and Wilcock, 2007; ABPI Medicines Compendium, 2008b]