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. Some chronic non-malignant conditions benefit from analgesic control with opioids, but patients should be reviewed regularly. Opioids are increasingly prescribed for non-cancerous conditions but it may be appropriate to involve a specialist in the decision to prescribe long-term opioids for such conditions.
Dosage instructions, side-effects, contra-indications and warnings
See individual drug monographs for further details.
Choice of opioid
- Codeine or dihydrocodeine are useful for mild to moderate pain, but the side-effects (nausea and constipation) make them unsuitable for long-term use. There maybe inter-individual variations in effectiveness to codeine as a result of genetic polymorphisms of cytochrome P450 enzymes leading to differing levels of metabolism.
- 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 pain, 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. A Cochrane review concluded 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. Buprenorphine is available as a transdermal patch, and is a useful alternative to fentanyl patches (see below).
- Dipipanone is less sedating than morphine but is only available in the UK in combination with the anti-emetic cyclizine. Adverse effects of the cyclizine component 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.
- 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.
- Oxycodone used to be considered to have equal analgesic potency to that of morphine. However, trials have made it clear that it has a higher bioavailability and a slightly longer duration of action. 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.
- 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.
- 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, makes it less suitable than other opioids for prolonged obstetric analgesia.
- Alfentanil, fentanyl and remifentanil are used in injectable form for postoperative analgesia. Fentanyl is also available as a self-adhesive patch.
- 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, numerous randomly controlled small trials do demonstrate a subgroup of patients who derive benefit.
- 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.
- The concept of cross-tolerance also needs to be taken into account.
- 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%.
- Morphine to methadone - trials have suggested 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.
- 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.
- 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.
|Equianalgesic doses* used in calculating opioid switches|
|Drug||Equianalgesic Dose (mg)**|
|Sustained-release morphine||20-60 po|
|Fentanyl||0.1 IV or SC|
- 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, which is then maintained for an average of 17 hours. A 72-hour matrix patch is also available.
- 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:
- 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.
- 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 also available in a transdermal formulation and has proved effective and well tolerated in controlled trials. One study showed that patients prescribed transdermal buprenorphine underwent fewer dosage changes than patients prescribed transdermal fentanyl. 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.
|Switching from morphine to fentanyl transdermal patches|
|Oral morphine 60-134 mg daily||fentanyl '25' patch|
|Oral morphine 135-224 mg daily||fentanyl '50' patch|
|Oral morphine 225-314 mg daily||fentanyl '75' patch|
|Oral morphine 315-414 mg daily||fentanyl '100' patch|
The situation with buprenorphine is less clear, and may vary according to the length of previous opioid administration, but the equipotency (dose required to obtain the same degree of analgesia) compared to oral morphine has been quoted as being between 1:75 and 1:115.
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:
- 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 should sign and date the prescription.
- A prescription may order a controlled drug 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 (DH) reduced the maximum permissible duration of Schedule 2 and 3 drug prescriptions from 13 weeks to 28 days in June 2006.
The DH has withdrawn the requirement that all prescriptions for controlled drugs should be handwritten since 2007. 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, but 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 0.4-2 mg IV, repeated at 2- to 3-minute intervals to a maximum of 10 mg (child 10 micrograms/kg, subsequent dose 100 micrograms/kg if no response).
- 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 subcutaneous 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 - 10 mg diluted in 50 ml IV fluid solution.
- The initial rate should be set at 60% of the IV 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 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 & references
- Ma JD, Lee KC, Kuo GM; Clinical application of pharmacogenomics. J Pharm Pract. 2012 Aug;25(4):417-27. doi: 10.1177/0897190012448309. Epub 2012 Jun 11.
- Wiffen PJ, McQuay HJ; Oral morphine for cancer pain. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003868.
- Hanks G, Cherny N, Calman K; Opioid Analgesic Therapy, Oxford Textbook of Palliative Medicine, Third Edition, 2005
- Nicholson AB; Methadone for cancer pain. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003971.
- Lugo RA, Kern SE; The pharmacokinetics of oxycodone.; J Pain Palliat Care Pharmacother. 2004;18(4):17-30.
- Riley J, Eisenberg E, Muller-Schwefe G, et al; Oxycodone: a review of its use in the management of pain. Curr Med Res Opin. 2008 Jan;24(1):175-92.
- Muriel C, Failde I, Mico JA, et al; Effectiveness and tolerability of the buprenorphine transdermal system in patients with moderate to severe chronic pain: a multicenter, open-label, uncontrolled, prospective, observational clinical study.; Clin Ther. 2005 Apr;27(4):451-62.
- Challoner KR, McCarron MM, Newton EJ; Pentazocine (Talwin) intoxication: report of 57 cases.; J Emerg Med. 1990 Jan-Feb;8(1):67-74.
- Riley J, Ross JR, Rutter D, et al; No pain relief from morphine? Individual variation in sensitivity to morphine and the need to switch to an alternative opioid in cancer patients.; Support Care Cancer. 2006 Jan;14(1):56-64. Epub 2005 Jun 11.
- Ripamonti C, Groff L, Brunelli C, et al; Switching from morphine to oral methadone in treating cancer pain: what is the equianalgesic dose ratio?; J Clin Oncol. 1998 Oct;16(10):3216-21.
- Dosing and conversion chart for opioid analgesics; American College of Physicians, 2004
- Poulain P, Denier W, Douma J, et al; Efficacy and safety of transdermal buprenorphine: a randomized, placebo-controlled trial in 289 patients with severe cancer pain. J Pain Symptom Manage. 2008 Aug;36(2):117-25. Epub 2008 Apr 14.
- Likar R, Kayser H, Sittl R; Long-term management of chronic pain with transdermal buprenorphine: a multicenter, open-label, follow-up study in patients from three short-term clinical trials. Clin Ther. 2006 Jun;28(6):943-52.
- Sittl R, Nuijten M, Nautrup BP; Changes in the prescribed daily doses of transdermal fentanyl and transdermal buprenorphine during treatment of patients with cancer and noncancer pain in Germany: results of a retrospective cohort study.; Clin Ther. 2005 Jul;27(7):1022-31.
- Sittl R, Nuijten M, Nautrup BP; Patterns of dosage changes with transdermal buprenorphine and transdermal fentanyl for the treatment of noncancer and cancer pain: a retrospective data analysis in Germany. Clin Ther. 2006 Aug;28(8):1144-54.
- Manufacturer's PIL, Durogesic® Dtrans® Transdermal Patch; Janssen-Cilag Limited; The electronic Medicines Compendium. Dated Febuary 2013.
- Sittl R, Likar R, Nautrup BP; Equipotent doses of transdermal fentanyl and transdermal buprenorphine in patients with cancer and noncancer pain: results of a retrospective cohort study.; Clin Ther. 2005 Feb;27(2):225-37.
- The Misuse of Drugs (Amendment No. 2) Regulations 2006; Statutory Instrument No. 1450 2006
- Controlled Drugs (Supervision of management and use) Regulations, Dept of Health, 2013
- O'Neill WM, Hanks GW, Simpson P, et al; The cognitive and psychomotor effects of morphine in healthy subjects: a randomized controlled trial of repeated (four) oral doses of dextropropoxyphene, morphine, lorazepam and placebo.; Pain. 2000 Mar;85(1-2):209-15.
|Original Author: Dr Laurence Knott||Current Version: Dr Gurvinder Rull||Peer Reviewer: Dr Adrian Bonsall|
|Last Checked: 02/05/2013||Document ID: 513 Version: 6||© EMIS|
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