Opioid analgesics are prescribed for moderate to severe pain, particularly of visceral origin. Evidence of efficacy and safety is strongest for use in acute pain and cancer-related pain. They are used in step two and step three of the World Health Organization (WHO) cancer pain ladder. Dependence and tolerance are well-known features with regular use although this should not necessarily inhibit prescribing in palliative care. Some people with chronic non-malignant conditions benefit from analgesic control with opioids, but prescribing should be reviewed regularly.
See individual drug monographs for further details, but there are contra-indications, cautions and side-effects common to all opioids.
Contra-indications common to all opioids:
- Acute respiratory depression.
- Head injury and/or raised intracranial pressure (opioids affect pupillary responses which are vital for neurological assessment).
- Risk of paralytic ileus.
Opioids may need to be avoided or the dose reduced in the following situations:
- Adrenocortical insufficiency.
- Acute attack of asthma.
- Convulsive disorders.
- Those who are elderly or debilitated.
- Diseases of the biliary tract.
- Impaired respiratory function.
- Inflammatory or obstructive bowel disorders.
- Myasthenia gravis.
- Prostatic hypertrophy.
- Urethral stenosis.
Regular use of opioids may be associated with development of tolerance, dependence or addiction. In a palliative care situation this should not necessarily prevent their use. Dependence and addiction are more likely to occur in people with comorbid mental health problems, including substance abuse.
Common side-effects of all opioids:
- Nausea and/or vomiting
- Dry mouth.
- Difficulty with micturition/urinary retention.
- Postural hypotension.
- Palpitations or bradycardia.
- Pruritus and/or rash.
- Mood changes.
- Respiratory depression (in larger doses).
- Biliary spasm.
Choice of opioid
- Codeine or dihydrocodeine is useful for mild to moderate pain but the side-effects (nausea and constipation) make them unsuitable for long-term use. Codeine is metabolised in the liver to morphine but there are individual variations in effectiveness due to differing rates of this metabolic process. Further variations may occur due to interactions with other medication and their effect on the relevant enzymes, either reducing conversion to morphine and thereby efficacy (eg, fluoxetine, paroxetine, duloxetine) or enhancing it (eg, dexamethasone, rifampicin).
- Tramadol is stronger than codeine and enhances serotonergic and adrenergic pathways as well as having an opioid effect. Adverse effects are probably comparative to codeine or dihydrocodeine.
- Meptazinol is a centrally acting opioid used for moderate to severe pain (including postoperative pain and renal colic) with both agonist and antagonist effects on opioid receptors. It causes less respiratory depression but caution is still warranted in anyone with a reduced respiratory drive.
- Morphine remains the most valuable option of the stronger opioids for the management of severe pain, although nausea and vomiting are frequent adverse effects. It causes feelings of detachment and euphoria, which are very useful in the management of anxiety in palliative care. Cochrane reviews continue to conclude that it should be considered first-line for moderate to severe cancer pain.
- Buprenorphine has a longer duration of action than morphine 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. There is a high incidence of vomiting and because it has both agonist and antagonist properties, it can precipitate withdrawal symptoms, including pain, in patients dependent on other opioids. The high affinity of buprenorphine for one type or opioid receptor site (mu) renders its effects only partially reversible by naloxone. A Cochrane review concluded buprenorphine could be considered a fourth-line option for cancer-related pain and that the sublingual and injectable routes could be demonstrated to have a more definable analgesic effect.
- Dipipanone is less sedating than morphine but is only available in the UK as a tablet in combination with the anti-emetic cyclizine. Adverse effects of the cyclizine component may make the combination unsuitable for long-term use.
- Diamorphine (heroin) may cause less hypotension and nausea than morphine. Its great solubility allows it to be delivered in smaller volumes than morphine. It may be given by intravenous, intramuscular or subcutaneous injection for severe pain.
- Methadone has a long half-life and hence a longer duration of action than morphine. This results in a higher risk of accumulation, so it is usually prescribed once daily. It is less sedating and is worth trying in some patients on morphine who have poor pain control or excessive adverse effects. Due to the risk of accumulation, adverse effects may have a delayed appearance. Studies looking at safety and efficacy for non-cancer pain have so far been inconclusive.
- Oxycodone has similar efficacy and adverse effects rates to morphine and can be considered an equal first-line option for cancer pain. There is only very low-quality evidence supporting its use in painful diabetic neuropathy and postherpetic neuralgia and none for other neuropathic pain conditions. It is available in capsule, slow-release tablet, oral solution and injectable and suppository forms in the UK.
- Pentazocine can precipitate withdrawal symptoms in patients dependent on other opioids, due to its agonist and antagonist properties. It is a weak analgesic in its oral form but in injectable form it is stronger than codeine or dihydrocodeine. Hallucinations, delusions and agitation can occur at higher doses. The haemodynamic effects of pentazocine make it unsuitable for use in myocardial infarction. It is only partially reversed by naloxone.
- Pethidine produces a faster onset but shorter duration of action than morphine. 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, make it less suitable than other opioids for prolonged obstetric analgesia.
- Tapentadol is a newer oral opioid with similar efficacy for cancer pain and side-effect profile to morphine and oxycodone.
- Alfentanil, fentanyl and remifentanil are used in injectable form for operative analgesia. Fentanyl is also available as a self-adhesive patch as an alternative to strong oral opioids such as morphine, and as buccal lozenges for breakthrough cancer-related pain. There is some evidence that transdermal fentanyl is associated with less constipation than oral morphine.
The value of opioid analgesia is greatest for acute pain (such as traumatic or postoperative) and in palliative care for cancer-related pain. For the most part when used for chronic long-term pain, adverse effects and the risk of dependence tend to outweigh the benefits, although there are individual differences and in some cases use in these conditions may be appropriate[14, 15].
- A significant minority of patients on strong opioids are unable to tolerate the side-effects or do not experience adequate pain control.
- Switching opioids should only be managed by a prescriber with experience in this area. A switch may be appropriate if pain relief is being achieved with an opioid but adverse effects are unacceptable, or if a different route of administration is required. For most people, if a single dose of immediate-relief morphine 20 mg does not cause significant reduction in pain, opioids are unlikely to be beneficial in the long term.
- When switching, it is helpful to think in terms of equianalgesic dose ratios. The equianalgesic dose is the dose which provides a degree of analgesia equivalent to 10 mg intramuscular (IM) morphine.
- If the patient is getting sufficient analgesia on the original opioid, the new drug should be introduced at an equianalgesic dose of 50-75% to account for tolerance and in the interests of safety. At high doses, a reduction of at least 50% is advised.
- If the reduction in dose is too great, withdrawal symptoms may occur.
- Charts with equivalent doses are available in the British National Formulary and in the Faculty of Pain Medicine/Public Health England resource "Opioids Aware".
- 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 used to the slower onset of oral medication and it may help to use both methods for 2-3 days. Changing from the subcutaneous (SC) to intravenous (IV) route may not need dosage alteration. 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.
- Oral morphine to subcutaneous morphine or subcutaneous diamorphine. As a guide, halve the 24-hour oral morphine dose to change to subcutaneous morphine. Use one third of the 24-hour oral morphine dose over 24 hours for diamorphine.
- Normal-release to sustained-release preparations - sustained-release formulations of oral morphine sulfate, 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.
- Rescue dosing - The dose of a strong opioid for breakthrough pain is usually one tenth to one sixth of the regular 24-hour dose, repeated every 2-4 hours as required (up to hourly may be needed if pain is severe or in the last days of life). Rescue doses should be taken into account when titrating doses upwards or switching opioid preparations.
|Equianalgesic doses used in calculating opioid switches for oral opioids|
|Drug||Equianalgesic dose (mg), ie the dose which compares to 10 mg po of morphine (Potency Ratio compared to morphine in brackets)|
|Morphine||10 mg (1)|
|Dihydrocodeine||100 mg (0.1)|
|Codeine||100 mg (0.1)|
|Hydromorphine||1.3 mg (7.5)|
|Oxycodone||5 mg (2)|
|Tapentadol||25 mg (0.4)|
|Tramadol||67 mg (1.5)|
|Methadone||Under specialist supervision only|
- The opioid patch is 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. Patches are replaced every 72 hours.
- 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.
- Transdermal patches may be unsuitable for patients with unstable pain who require rapid changes in dosage, and some patients have difficulties with patch adhesion.
- The kinetics of transdermal delivery systems means that the following have to be taken into account:
- 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 SC depots after the patch is removed.
- An increase in opioid concentration can occur if the skin temperature is raised - eg, if the patient is febrile.
- Approximate equivalent doses are listed in the tables below from the British National Formulary; however, as per the information above, when switching from another opioid, the dose should be reduced by 25-50%.
|Approximate equivalent dose of morphine to 72-hour fentanyl transdermal patches|
|Oral morphine 30 mg daily||fentanyl '12' patch|
|Oral morphine 60 mg daily||fentanyl '25' patch|
|Oral morphine 120 mg daily||fentanyl '50' patch|
|Oral morphine 180 mg daily||fentanyl '75' patch|
|Oral morphine 240 mg daily||fentanyl '100' patch|
|Approximate equivalent dose of morphine to buprenorphine transdermal patches|
|Oral morphine 12 mg daily||Buprenorphine '5' patch (7-day patch)|
|Oral morphine 24 mg daily||Buprenorphine '10' patch (7-day patch)|
|Oral morphine 48 mg daily||Buprenorphine '20' patch (7-day patch)|
|Oral morphine 84 mg daily||Buprenorphine '35' patch (4-day patch)|
|Oral morphine 126 mg daily||Buprenorphine '52.5' patch (4-day patch)|
|Oral morphine 168 mg daily||Buprenorphine '70' patch (4-day patch)|
Many opioids are classified under Schedule 2 of the Drugs Misuse Act. Buprenorphine, tramadol and pentazocine come under Schedule 3 and codeine and dihydrocodeine come under Schedule 5. Prescriptions for controlled drugs need to include:
- The 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's signature and the date of the prescription.
- No repeat ordering: prescriptions ordering repeats on the same form are not permitted.
The Department of Health (DH) reduced the maximum permissible duration of Schedule 2, 3 and 4 drug prescriptions to 30 days in June 2006.
The DH has withdrawn the requirement that all prescriptions for controlled drugs should be handwritten since 2007. More recently, amendments to regulations allow the signature on a prescription for a controlled drug to be electronic if the Electronic Prescribing Service (EPS) is used. A recent update to the DH guidance on supervision and management of the use of controlled drugs is the introduction of Controlled Drugs Accountable Officers, who will supervise the overall safe use of controlled drugs across health organisations.
Opioids and driving
- Patients should be warned about the effects of opioids on skilled tasks such as driving.
- 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; however, for patients who are stable and alert, driving may be possible.
Treating opioid overdose
- The signs of significant opioid overdose are pinpoint pupils, respiratory depression and coma.
- 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 400 micrograms IV, then 800 micrograms for up to 2 doses at 1-minute intervals if no response to preceding dose, then increased to 2 mg for 1 dose if still no response. (Child up to the age of 12, initially 100 micrograms - if no response, repeat at intervals of 1 minute to a total max. 2 mg.)
- In certain scenarios it may be more advisable to use smaller doses of naloxone (such as 50 micrograms every few minutes), especially if there are concerns that abolishing all opioid effects may lead to significant problems for the patient - eg, pain or opioid withdrawal syndrome.
- Alternatively, the SC or IM route can be used - adult and child dose as for IV injection. However, 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 IV infusion can be set up using an infusion pump.
- 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 is 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.
Further reading and references
Stannard C; Opioids in the UK: what's the problem? BMJ. 2013 Aug 15347:f5108. doi: 10.1136/bmj.f5108.
Palliative care for adults: strong opioids for pain relief; NICE Clinical Guideline (May 2012)
Opioids Aware: A resource for patients and healthcare professionals to support prescribing of opioid medicines for pain; Faculty of Pain Medicine/Public Health England
WHO's cancer pain ladder for adults; World Health Organization (WHO)
British National Formulary (BNF); NICE Evidence Services (UK access only)
Straube C, Derry S, Jackson KC, et al; Codeine, alone and with paracetamol (acetaminophen), for cancer pain. Cochrane Database Syst Rev. 2014 Sep 19(9):CD006601. doi: 10.1002/14651858.CD006601.pub4.
Wiffen PJ, Wee B, Moore RA; Oral morphine for cancer pain. Cochrane Database Syst Rev. 2016 Apr 224:CD003868. doi: 10.1002/14651858.CD003868.pub4.
Hanks G, Cherny N, Calman K; Opioid Analgesic Therapy, Oxford Textbook of Palliative Medicine, Third Edition, 2005
Schmidt-Hansen M, Bromham N, Taubert M, et al; Buprenorphine for treating cancer pain. Cochrane Database Syst Rev. 2015 Mar 31(3):CD009596. doi: 10.1002/14651858.CD009596.pub4.
Nicholson AB; Methadone for cancer pain. Cochrane Database Syst Rev. 2007 Oct 17(4):CD003971.
Haroutiunian S, McNicol ED, Lipman AG; Methadone for chronic non-cancer pain in adults. Cochrane Database Syst Rev. 2012 Nov 1411:CD008025. doi: 10.1002/14651858.CD008025.pub2.
Schmidt-Hansen M, Bennett MI, Arnold S, et al; Oxycodone for cancer-related pain. Cochrane Database Syst Rev. 2015 Feb 27(2):CD003870. doi: 10.1002/14651858.CD003870.pub5.
Gaskell H, Derry S, Stannard C, et al; Oxycodone for neuropathic pain in adults. Cochrane Database Syst Rev. 2016 Jul 287:CD010692. doi: 10.1002/14651858.CD010692.pub3.
Wiffen PJ, Derry S, Naessens K, et al; Oral tapentadol for cancer pain. Cochrane Database Syst Rev. 2015 Sep 25(9):CD011460. doi: 10.1002/14651858.CD011460.pub2.
Hadley G, Derry S, Moore RA, et al; Transdermal fentanyl for cancer pain. Cochrane Database Syst Rev. 2013 Oct 510:CD010270. doi: 10.1002/14651858.CD010270.pub2.
da Costa BR, Nuesch E, Kasteler R, et al; Oral or transdermal opioids for osteoarthritis of the knee or hip. Cochrane Database Syst Rev. 2014 Sep 17(9):CD003115. doi: 10.1002/14651858.CD003115.pub4.
Noble M, Treadwell JR, Tregear SJ, et al; Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev. 2010 Jan 20(1):CD006605. doi: 10.1002/14651858.CD006605.pub2.
Controlled Drugs (Supervision of management and use) Regulations; Dept of Health, 2013
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