Opioid analgesics remain the mainstay of treatment for moderate to severe pain. All opioids, when given in equianalgesic doses, produce a similar analgesic effect. There is increasing concern regarding the over-use of opioids in the community. [1-3] Population trends have seen an increase in the prescription of opioids for non-cancer chronic pain and there has been a shift in trends associated with the prescription of opioids in life-limiting illnesses. There is an increasing use of analgesic prescriptions in aged care, including opioids used as slow release and as needed (pro re nata - prn). [4-6] Other areas have seen an increased trend in opioid prescription over time in haemodialysis.  Palliative care services are more likely to be referred patients already taking opioids and are more likely to prescribe opioids to their patients. [2,8] The more frequent use of opioids in palliative care may be associated with pain management, but also the use of opioids to treat other symptoms, such as dyspnoea.
Opioids are effective in treating nociceptive pain and there are several guidelines supporting this use in the palliative care setting.
Choice of Opioid
Several opioids are available in Australia, including morphine, codeine, oxycodone, hydromorphone, fentanyl, alfentanil, sufentanil, methadone, and buprenorphine. Atypical centrally acting analgesics, tramadol and tapentadol, are also available.
There are no important differences between oral morphine, oral oxycodone, and oral hydromorphone in analgesic efficiency and according to EAPC guidelines any of these can be used as the first line opioid.  Each opioid has slightly different side effects and some may be useful in certain conditions or with certain patient groups due to their individual properties. [9,10] The choice of opioid will depend on the available preparation, with some opioids available in transdermal, sublingual and buccal forms and should also be dependent on the discussion with patients on the benefits and risks of each option. 
Few trials have been designed to allow direct comparison between different opioids,  and use of opioids in palliative care is often based on research carried out in different cohorts and different clinical settings. Oral morphine is a common opioid used in cancer pain,  and remains a commonly prescribed opioid in adult and paediatric palliative care. [9,13,14] Fentanyl is also commonly prescribed due to its availability in transdermal and transmucosal form.  Oxycodone and hydromorphone are available in a number of preparations and are useful alternatives in patients who do not tolerate morphine.  Methadone has more complex pharmacokinetic and pharmacodynamic properties than other opioids and guidelines recommend caution when prescribing. [17-19]
There is limited quality evidence for the choice of opioid in paediatric populations. Codeine, a prodrug often prescribed as a combination medication with paracetamol, is less commonly used in palliative care. Since 2013 a number of serious warnings have been issued regarding its use in children due to the potential risk of over-metabolisation and adverse events.  Another prodrug, Tramadol has also been contraindicated in children under the age of 12.  Opioids, such as Fentanyl, Sufentanil and Alfentanil are frequently used in the paediatric population but have limited quality evidence on their pharmacokinetic properties.  Recent research has found Buprenorphine to be an effective analgesic in paediatric cancer pain and palliative care.  There has been an increase in the use of methadone in paediatric palliative care, particularly in patients with difficult to treat pain, but there is low quality evidence to support its use. 
Older patients, those over the age of 65, are potentially more sensitive to the effects of opioids due to physiological changes associated with aging.  No one opioid is superior in this group, although lower initial doses and slower titration is recommended. [12,23] Buprenorphine, a partial mu-opioid agonist, is a popular opioid choice in this group as it is available in a transdermal preparation and is believed to have fewer side effects, such as respiratory depression than other opioids.  However, a meta-analysis of patients prescribed buprenorphine over the age of 65 suggested adverse events were experienced by nearly 82 per cent of users. 
Patients with renal and hepatic failure are at greater risk of opioid induced side effects and therefore the choice of opioid may steer toward fentanyl or hydromorphone, as these opioids have fewer active metabolites.  Both alfentanil and sufentanil have been reviewed for use in patients with renal impairment with effective outcomes reported.  Recently the use of buprenorphine has been supported in patients with renal failure, yet evidence in this area remains of relatively low quality.  Fentanyl and hydromorphone are more commonly used in clinical practice in patients with hepatic dysfunction. 
Atypical, centrally acting analgesics, tramadol and tapentadol, work using a combined effect as an opioid agonist and a serotonin-and noradrenaline-reuptake inhibitor. Because of this unique mechanism of action the side effect profile of both tramadol and tapentadol are different from conventional opioids.  Both medications have been shown to provide comparable analgesia to single action mu agonist opioids in various cohorts but there is low quality evidence for their use in palliative care.  There is low quality evidence for the use of tramadol in neuropathic pain. 
Routes of Administration for Opioids
For the administration of opioids patient choice and their condition may guide the route of administration. As the patient’s condition deteriorates more invasive options could be considered to provide opioid analgesics.
The administration of opioids via the sublingual route is an area of research and innovation for pharmaceutical companies. Hydrophilic opioids, such as morphine, oxycodone and hydromorphone are poorly absorbed by this route, whereas, lipophilic opioids, fentanyl and methadone are well absorbed. Partial opioids such as buprenorphine and tramadol are also well absorbed via this route. Sublingual opioid medication is available in Australia for buprenorphine. There are sublingual preparations available for fentanyl in the United States.  A recent systematic review showed sublingual buprenorphine was as effective an analgesic as intramuscular and intravenous morphine.  Buccal fentanyl is commonly used in the palliative care and oncology setting for breakthrough pain. [15,32]
When the oral route is not appropriate or no longer effective, subcutaneous or intravenous infusions of opioids or patient controlled analgesia have been shown to be effective.  Many opioids are available via these routes and although neither has a superior analgesic profile the intravenous route may have a higher risk of infection. Patient controlled analgesia, via subcutaneous or intravenous route, has been demonstrated to be an effective way to administer opioids in a palliative care setting for adults and children. [33,34]
An alternative to the oral route is transdermal and both fentanyl and buprenorphine have been used in cancer pain and palliative care for some time. [15,35] While both medications are efficacious when compared to slow release oral morphine, transdermal buprenorphine has demonstrated fewer side effects than transdermal fentanyl. 
Fentanyl and alfentanil have also been delivered via the intranasal route where a non-invasive, rapid onset, non-oral option is required.  The use of intranasal fentanyl in paediatric pain,  cancer pain, [15,32] breakthrough pain [32,36] and procedural pain  is well established. Intranasal fentanyl has also been proven to be effective in perinatal palliative care. 
Neuraxial opioids could also be considered to manage severe pain not responding to other treatments. A common route of administration in the post-operative setting via epidural, neuraxial opioids delivered via intrathecal pumps and catheters were also commonly used in the management of chronic pain.  These have been used in cancer and palliative care, although the research to support these modalities is limited. This might be because the technique to use this modality is extremely specialised and therefore not readily available. 
Topical opioids have been studied for use in ulcers (both malignant and non-malignant) and in oropharyngeal mucositis, and appear likely to be effective, although the evidence is of varied quality, and further investigation is needed. [40,41]
Managing opioid adverse effects, whether by preventing or treating them, is an important aspect of clinical practice. All opioids have the potential to cause adverse effects and some effects may be dose dependent or patient specific. Titration of opioid dose is useful to minimise adverse effects as is the use of opioid sparing techniques with multimodal analgesic approaches.
Nausea and Vomiting
Much of the research generated on opioid-induced nausea and vomiting comes from an acute and post-operative clinical setting. A recent systematic review of nausea and vomiting associated with opioids identified limited evidence to support the practice of opioid rotation or switching.  The EAPC guidelines recommend the use of antidopaminergic drugs (eg, haloperidol or metoclopramide) for treatment of this problem.  There is limited specific evidence for antiemetic choice in older people or paediatrics.
GI Motility/ Constipation
Opioids reduce gastrointestinal motility and a common adverse effect with prolonged use is constipation. [12,43] There are a number of guidelines available for clinicians on the management of opioid-induced constipation. [44,45] Early identification, improved fluid intake and the use of laxatives are supported where clinically appropriate.  A recent systematic review on pharmacological therapies for opioid-induced constipation, specifically in a palliative care context, found naloxone as a single agent or in combination with oxycodone (Targin) had low quality evidence to support its use.  Other medications such as nalmedine (not currently available in Australia) and methylnaltrexone had moderate levels of evidence to support their use.  Systematic reviews not specifically refined to palliative care support the use of naloxone. 
Urinary retention is recognised as a common problem in palliative care, and in the use of opioids, although patients at the end of life may have urinary retention not associated with any opioid use.  Reduction in opioid dose or rotation to an alternative opioid may be beneficial. 
Opioid induced pruritus is a potential adverse reaction that can greatly affect the quality of life of a patient within the palliative care environment. As with other symptoms pruritus may not be opioid-induced and is a common symptom in some cancers  and in end stage liver failure and in renal failure.  Treatment with opioid reduction or rotation may be beneficial, although the use of small dose naloxone has been examined recently in palliative care.  This has been an established treatment approach in the acute setting and more research is needed to establish efficacy in the palliative care cohort.
The sedative effects of opioids are considered a continuum of effect, but the development of cognitive impairment and / or delirium is outside this continuum. This adverse effect could be grouped with opioid-induced hyperalgesia as a symptom of opioid-induced neurotoxicity  which arises, often, from the escalation of opioid doses and particularly the accumulation of opioid metabolites.  Opioid induced neurotoxicity occurred in up to 15 per cent of palliative care patients in one study.  Older patients and patients with renal insufficiency may be more susceptible to opioid accumulation and therefore to opioid induced neurotoxicity.  The most common treatment approach to managing opioid induced neurotoxicity is opioid rotation, with one systematic review suggesting methadone may an effective choice of opioid, although the evidence is of low quality. 
Other Adverse Effects
There has been a suggestion that opioids may interfere with the function of the immune system and that cancer patients receiving opioids for a prolonged period of time may have a reduced survival time.  A recent review of the evidence has found little to support this theory.  The use of methadone has increased within the palliative care context and its use in the general population has been linked to the development of serious cardiac issues, namely the prolongation of the QT interval.  This issue may be exacerbated by the use of other medications which also effect the QT interval. 
Opioid Rotation / Switching
To avoid or reduce the impact of adverse effects 'opioid rotation or switching' is a common approach. Inter-individual variations in pharmacokinetics and pharmacodynamics of the different opioids available are likely to be significant in patients’ individual responses to opioid medications. Some organisations have recommended limits to the daily morphine equivalent dose, using a time limited prescription in acute pain and tapering opioids in chronic non-cancer pain.  In palliative care the application of opioid rotation, particularly in cancer pain and at the end of life, is often done to improve analgesia and reduce adverse effects rather than reduce the total daily opioid dose.  The EAPC guidelines offer a weak recommendation for opioid rotation.  Due to the individual nature of the response to opioids equianalgesic conversion tables should be used as a guide. The Faculty of Pain Medicine recommends caution when using dose equivalence tables.  A challenging area of practice relates to opioid rotation to and from methadone, and most guidelines recommend caution due to methadone’s unique properties. [19,56,59] A study of conversion ratios used to switch patients to methadone from other opioids revealed that, of the many methods in clinical use, none seems to be superior to any other.  Clinical expertise and careful monitoring are needed in the use of methadone. 
Opioid Dependence and Abuse
The increase in opioid use within general population and the trends for earlier referral to palliative care mean patients may be attending a palliative care service longer than was previously experienced. There may be a need to evaluate the prescription of opioids. Palliative care services are likely to treat patients with chronic pain conditions as well as those with previously diagnosed drug dependence, patients currently accessing drug dependence programs and those with a history of drug abuse.  Opioid risk assessment tools have been used for some time in chronic pain services to screen for the risk of addiction and have also been applied to palliative care.  Opioid addiction and medication abuse is a complex process which requires screening and monitoring.
Choosing the First Line Opioid
Morphine has been widely recommended due to its efficacy, easy availability, versatility, cost, and the extensive clinical experience of using it in palliative care patients; however, there is no evidence that it is superior to other opioids.  Morphine, oxycodone, and hydromorphone are clinically similar in terms of efficacy and adverse effects. [9,57] Choice of opioid is based on specific properties of the drug and preparation (eg, versatility of various routes of administration, availability of sustained and immediate release formulations, cost to the patient and the healthcare system).  Methadone and transdermal preparations are not recommended as first-line opioids. [9,62] Morphine, oxycodone and hydromorphone all have metabolites that are likely to accumulate in renal impairment. However, of these agents, there is extensive experience of successfully using hydromorphone in renal patients. Unwanted side effects due to accumulation of morphine metabolites may be satisfactorily dealt with by either increasing the dosing interval or reducing the 24-hour dose or by switching to an alternative opioid. [17,57] Methadone, fentanyl and buprenorphine have less risk of accumulation.  However methadone has complex pharmacokinetics and a long and unpredictable half-life  and fentanyl has less versatility in the preparations which are available, and significant potential for drug interactions. 
Opioid Initiation and Titration
There are a number of guidelines available to guide clinical decision making regarding initial dose choice and titration of dosing of opioids. There is low quality evidence to guide practice and commonly guidelines are written by expert consensus. There is limited evidence that titration of opioid be achieved by exact ratios or calculated as a percentage of the initial dose.  The individual requirements of the patient should guide decision making as many patients may be referred to palliative care services already using some form of analgesic.  Initial dose recommendations will be altered by the patients age,  renal function,  liver function  and general condition.  Evidence supports low initial doses and slower dose titration in children,  older people  and in patients with renal and liver dysfunction.
Breakthrough pain occurs for many reasons in a patient receiving palliative care and is thus called as it is transient pain that ‘breaks through’ the stable, controlled background pain the patient may be experiencing. The incidence of breakthrough pain in cancer pain is as high as 60 per cent.  Consensus recommendations on breakthrough pain in cancer patients are available.  Providing an immediate-release opioid as needed to be used as a 'rescue dose' is recommended [36,65] Evidence supports current guideline recommendations for individual titration of breakthrough doses.  This contrasts with previous advice that breakthrough opioids should be prescribed in a fixed ratio to background opioids, The route of administration of an opioid for breakthrough pain is important, and where possible should match the time profile of the pain. Sublingual and intranasal preparations provide the fastest onset for patients but intranasal preparations may not be tolerated by some patient groups or individuals. [15,21] Transmucosal fentanyl is supported by moderate levels of evidence.  Even though it is the most commonly recommended approach to managing breakthrough pain,  there is little evidence to support the oral route as effective in providing breakthrough analgesia.  Clinicians should also address and treat reversible causes of breakthrough pain and background analgesia and adjuvant medications should be reviewed.  There is limited evidence for the use of pre-emptive opioids for breakthrough pain. [32,36]
Combining Strong Opioids
Weak evidence is available to support the practice of using several opioids in combination. Wherever possible the same opioid should be used for background pain and breakthrough pain.  This may not always be possible due to some opioids not being available in certain formulations.
Neuropathic pain is a significant problem for many palliative care patients and has been thought to be only partially responsive to opioids. The use of opioids to manage neuropathic pain is not recommended.  There is limited evidence for the use of tramadol in neuropathic pain  and other opioids are considered third line approaches. There is no conclusive evidence to support the use of tapentadol in neuropathic pain. 
- There are no important differences between oral morphine, oral oxycodone, and oral hydromorphone in analgesic efficiency and according to EAPC guidelines any of these can be used as the first line opioid. Morphine, oxycodone and hydromorphone are clinically similar in regard to adverse effects.
- Methadone and transdermal preparations are not recommended as first-line opioids. Methadone has complex pharmacokinetics and a long and unpredictable half-life and should be prescribed by experienced clinicians.
- Fentanyl, buprenorphine and methadone, are associated with less risk of metabolite accumulation in renal failure and are therefore recommended for use in this patient group.
- All opioids have the potential to cause adverse effects and some effects may be dose dependent or patient specific. Titration of opioid dose is useful to minimise adverse effects as is the use of opioid sparing techniques with multimodal analgesic approaches.
- Opioid dose conversion ratios are not fixed but are affected by the clinical context of the rotation and the setting of care. [10,56] When rotating/switching opioids, frequent clinical review and reassessment of pain and adverse effects is the safest approach. Based on studies of opioid rotation, it is important to individualise all opioid conversions.
- Providing an immediate-release opioid as needed to be used as a 'rescue dose' is recommended and individual titration of breakthrough doses is now recommended. [32,36]