Opioid Analgesics

Opioid analgesics are prescribed for moderate to severe pain, particularly of visceral origin, and are used in step two and step three of the analgesic ladder. Dependence and tolerance are well known features with regular use although this should not inhibit prescribing in palliative care.¹ Some chronic non-malignant conditions benefit from analgesic control with opioids, but patients should be reviewed regularly. One study showed that there has been a general increase in opioid prescribing for a wide spectrum of non-cancer conditions.² It may be appropriate to involve a specialist in the decision to prescribe opioids long term for such conditions.

See individual drug monographs for further details.

• Codeine or dihydrocodeine are useful for mild to moderate pain, but the side effects of nausea and constipation make them unsuitable for long-term use.³
• Tramadol enhances serotonergic and adrenergic pathways as well as having an opioid effect. Comparative trials suggest it has a better analgesic effect than codeine⁴ without an increase in adverse effects.⁵
• Meptazinol is claimed to have a low incidence of respiratory depression⁶ but the evidence base is not convincing.⁷
• Morphine remains the most valuable option of the stronger opioids for the management of severe pain, although nausea and vomiting are frequent adverse effects.⁸ It causes feelings of detachment and euphoria, which are very useful in the management of anxiety in palliative care.⁹ A Cochrane review concluded that it should be considered first-line for moderate to severe cancer pain.¹⁰
• Buprenorphine has a longer duration of action than morphine¹¹ and has an effect sublingually for 6-8 hours. It is however less effective than morphine and needs a high concentration to achieve a reasonable degree of analgesia.⁹ There is a high incidence of vomiting,⁹ and because it has both agonist and antagonist properties, it can precipitate withdrawal symptoms, including pain, in patients dependent on other opioids.¹² The high affinity of buprenorphine for one type or opioid receptor site (mu) renders its effects only partially reversible by naloxone.¹³ Buprenorphine is available as a transdermal patch, and is a useful alternative to fentanyl patches (see below).
• Dipipanone is less sedating than morphine. However it is only available in the UK in combination with the anti-emetic cyclizine, and the sedating and anticholinergic effects of the latter makes the combination unsuitable for long-term use.⁹
• Diamorphine (heroin) may cause less hypotension and nausea than morphine.¹⁴ Its great solubility allows it to be delivered in smaller volumes than morphine, which may be important in the emaciated patient.⁸
• Methadone has a long half-life and hence a longer duration of action than morphine.⁹ This results in a higher risk of accumulation, so dosage should be restricted to twice a day if the drug is to be used for any length of time.¹⁵ It is less sedating, and is worth trying in some patients on morphine who have poor pain control or excessive adverse effects.¹⁶ One study concluded that it was useful in chronic non-cancer pain if prescribed by specialists who were well-versed in its use.¹⁷
• Hydromorphone is sometimes used as an alternative to morphine and is five times more potent.¹⁸
• Oxycodone used to be considered as having equal analgesic potency as morphine. However, recent trials have made it clear that it has a higher bioavailability and a slightly longer duration of action.^19,20 It is available in suppository form in the UK. It may be particularly suitable in palliative care patients as part of an opioid rotation scheme, in patients with morphine-induced hallucinations, and in patients with renal dysfunction.²¹
• Pentazocine can precipitate withdrawal symptoms in patients dependent on other opioids, due to its agonist and antagonist properties.²² It is a weak analgesic in its oral form, but in injectable form it is stronger than codeine or dihydrocodeine.¹³ Hallucinations, delusions and agitation can occur at higher doses.²³ The haemodynamic effects of pentazocine make it unsuitable for use in myocardial infarction.²⁴
• Pethidine produces a faster onset but shorter duration of action than morphine.⁹ It is therefore not suitable for chronic cancer pain. It has its uses during the last stage of labour,but its relatively modest analgesic effect combined with its potential to cause convulsions, makes it less suitable than other opioids for prolonged obstetric analgesia.²⁵ The use of diamorphine is increasing in consultant-led units in the UK but further trials are needed to assess the relative merits of the two drugs for this indication.²⁶
• Alfentanil, fentanyl and remifentanil are used in injectable form for post-operative analgesia. Fentanyl is also available as a self-adhesive patch.²⁷

• A significant minority of patients on strong opioids are unable to tolerate the side effects or do not experience adequate pain control.
• Current practice is to switch to another opioid, and whilst there are no meta-analyses to support such a switch,²⁸ numerous randomly-controlled small trials do demonstrate a subgroup of patients who derive benefit.^29,30
• When switching, it is helpful to think in terms of equianalgesic dose ratios.¹³ The equianalgesic dose is the dose which provides a degree of analgesia equivalent to 10 mg IM morphine. tolerance to another ('incomplete' tolerance).
• The concept of cross-tolerance also needs to be taken into account. Tolerance to one opioid does not guarantee the same degree of
• If the patient is getting sufficient analgesia on the old opioid, the new drug should be introduced at an equianalgesic dose of 50-75% to account for this.
• If analgesia was insufficient with the old drug, the equianalgesic dose of the new drug needs to be 75-100%.¹³

Common switches

• Morphine to methadone - recent trials suggest that methadone is much more potent than was once thought, and that the total amount of morphine taken before the switch has a significant effect on the equianalgesic dose ratio. In patients receiving low doses of morphine, the ratio is 4:1. In patients receiving a high dose (more than 300 mg oral morphine or parenteral equivalent) the ratio is closer to 10:1.³¹
• Changing the route of administration - when changing from the oral to the parenteral route or vice versa, the dose may need to be adjusted to avoid over- or under-dosing (see table). Patients may need to get use to the slower onset of oral medication, and it may help to use both methods for 2-3 days. Changing from the subcutaneous to intravenous route may not need dosage alteration.⁹ Switching from the oral to the parenteral route is usually done for patients with swallowing difficulties or vomiting. There does not appear to be any value in switching the method of administration in terms of efficacy. Trials do however demonstrate a lower incidence of adverse effects such as constipation, nausea and drowsiness.³²
• Normal-release to sustained release preparations - sustained release formulations of oral morphine sulphate, oral oxycodone, and transdermal fentanyl are commonly used in palliative care. Once the total daily opioid dose requirement is known, switching to the equivalent sustained release preparation can be done on a milligram for milligram basis. Rescue analgesia with a short-acting normal-release opioid can be given as required.⁹

• The opioid patch is basically a drug reservoir separated from the skin by a membrane. The drug is released over a period of time.
• For fentanyl, it takes approximately 12-24 hours to achieve maximum dosage, which is then maintained for an average of 17 hours, before decreasing.¹³ A new 72 hour matrix patch which delivers 35%-50% reduction of the absolute fentanyl content compared with other currently available transdermal fentanyl patches has recently been developed.³⁴
• Transdermal patches are mainly used for patients who are intolerant of oral medication, comply poorly with oral medication, or who react unfavourably to other opioids.
• The kinetics of transdermal delivery systems means that the following have to be taken into account:⁹
  • Additional analgesia (usually morphine) may need to be provided in the initiating period.
  • The first patch should be put on early in the day so the patient can be observed, to avoid overdosing during sleep.
  • Significant amounts of opioid can be released from tissue and subcutaneous depots after the patch is removed.
  • An increase in opioid concentration can occur if the skin temperature is raised, e.g. if the patient is febrile.
• Transdermal patches may be unsuitable for patients with unstable pain who require rapid changes in dosage, and some patients have difficulties with patch adhesion.
• Buprenorphine is now available in a transdermal formulation and has proved effective and well tolerated in controlled trials.^35,36 A 72 hour patch is now available.³⁷ One study showed that patients prescribed transdermal buprenorphine underwent fewer dosage changes than patients prescribed transdermal fentanyl.³⁸ A follow-up study confirmed this, and endorsed the previously held belief that buprenorphine may have a lower association with tolerance development than other strong opioids.³⁹

All opioids are classified under Schedule 2 of the Drugs Misuse Act, apart from buprenorphine which comes under Schedule 3.
Prescriptions for controlled drugs need to include:

• Patient's full name, address and age, where appropriate.
• Name and form of the drug, even if only one form exists.
• The strength of a preparation, where appropriate.
• The dose to be taken.
• The total quantity to be supplied in words and figures.
• The prescriber should sign and date the prescription.
• A prescription may order a CD to be dispensed by instalments, but must specify the amount of the instalments and the intervals to be observed. Prescriptions ordering repeats on the same form are not permitted. The Department of Health reduced the maximum permissible duration of Schedule 2 and 3 drug prescriptions from 13 weeks to 28 days in June 2006.⁴²

The Department of Health has withdrawn the requirement that all prescriptions for controlled drugs should be hand-written.⁴³

• Patients should be warned about the effects of opioids on skilled tasks such as driving.
• The mere fact that the patient is taking an opioid should not automatically preclude the possibility of driving,⁹ and it may be beneficial to their quality of life and morale that they continue to do so. As with all medication, however, it is the patient's responsibility not to drive if they feel unfit to do so. Sedation is more likely to occur on initiating opioids and changing dosages, but for patients who are stable and alert, driving may be possible.⁴⁴

• The signs of significant opioid overdose are pinpoint pupils, respiratory depression and coma.⁴⁵
• The specific antidote naloxone is indicated if coma or bradypnoea are present.
  • Close monitoring and repeated injections may be necessary, depending on response, as naloxone is a shorter acting drug than many opioids.
  • The initial starting dose is 0.4-2 mg IV, repeated at 2-3 minute intervals to a maximum of 10 mg (child 10 mcg/kg, subsequent dose 100 mcg/kg if no response).
  • Alternatively, the subcutaneous or intramuscular route can be used, adult and child dose as for intravenous injection, but these routes are less suitable due to slower onset of action.
  • If it is thought likely from the outset that repeated doses of naloxone may be needed, a continuous intravenous infusion can be set up using an infusion pump, 10 mg diluted in 50 ml intravenous fluid solution.
  • The initial rate should be set at 60% of the intravenous injection dose in one hour.
• The situation concerning palliative care is slightly different from that of acute overdose due to drug abuse.
  • The principal concern in patients on chronic opioid medication for pain control the advent of respiratory depression and sedation.
  • Naloxone can precipitate a severe abstinence syndrome characterised by sweating, restlessness, hypertension, muscle cramps and tachypnoea.
  • If the patient is bradypnoeic but rousable and the peak plasma level of the last opioid dose has been reached, the next dose should be withheld and the patient monitored.
  • Naloxone should only be considered in the event of severe hypoventilation or bradypnoea with coma, and then only in dilute form (1:10).
  • Endotracheal intubation may be necessary prior to naloxone administration to prevent aspiration.⁹