5.3.3 Opioid analgesics. Table II summarizes the Key points relating to opioid analgesics used in the UK
Table II. Key points to compare opioids for analgesia used in UK.
|Opioid||Receptors||Routes||Equivalent 24-h dose (30mg oral morphine/day as reference point)||Advantages||Disadvantages||Renal failure||Hepatic failure||Other information|
|Morphine||MOR agonist||PO, IV, SC, Sp||30 mg PO = 15 mg SC, IV||Familiarity; Cheap; Available as normal release and modified release tablets||Sedation; Hallucinations; Nausea; Constipation; Immunosuppression||Do not use – high risk of toxic metabolites in renal failure||Caution if prothrombin time prolonged||Nausea usually resolves – CNS side-effects and constipation usually persist|
|Tramadol||MOR agonist; SNRI||PO, IM||150 mg PO (maximum recommended dose is 400 mg per 24 h)||Less constipation than morphine; SNRI action may help with neuropathic painMay be immune-enhancing||Risk of serotonin syndrome with other SNRIs||Caution||Caution||Efficacy highly dependent on CYP2D6 phenotype; SNRI activity blocked by 5HT3 antagonists|
|Codeine||MOR agonist||PO||300 mg PO (NB – this is higher than maximum daily dose of 240 mg)||Familiarity; available without prescription||Constipation; Sedation||Do not use – as for morphine||Caution – as for morphine||Pro-drug of morphine; CYP2D6 dependent; Often combined with paracetamol|
|Oxycodone||MOR, KOR agonist||PO, IV, SC||15 mg PO = 7·5 mg SC, IV||Reduced sedation, hallucinations cf morphine||Oral liquid unpleasant taste – use capsules; For parenteral use, concentrate (50 mg/ml) now available as substitute for diamorphine); Probably immune-neutral||Caution – plasma concentrations may rise||Safe||Females have greater response; CYP3A4 and CYP2D6 dependent|
|Fentanyl||MOR agonist||TM (buccal, sublingual, nasal), TD, IV, Sp||12 μg/h TD patch over 72 h||Reduced sedation, emesis, constipation cf morphine; Convenience of 3 d patch||TM applications very short-acting (1–2 h) – best reserved for incident (movement-related) pains and dressing changes, etc.; Probably immunoneutral||Safe in renal failure (Alternative for parenteral use is alfentanil)||Safe||Use rapid acting TM formulations with caution in patients with addictive tendencies; Affected by CYP3A4-acting drugs|
|Buprenorphine||Partial MOR, ORL1 agonist; KOR, DOR antagonist||TM (sublingual), TD, IV||20 μg/h TD patch over 7 d||Reduced respiratory depression; Convenience of patches (5–20 μg dose TD patches can last 7 d||Nausea with initiation of higher dose TD patch; TM tablet causes nausea||Safe||Safe||Ceiling dose for respiratory depression makes it safer for COPD patients; Does not reverse other MOR opioids at therapeutic doses|
|Diamorphine||MOR agonist||IV, SC||10 mg SC, IV||Familiarity; High water solubility||As for morphine||Do not use – as for morphine||Caution -as for morphine||Pro-drug of morphine; Has no advantages apart from high water solubility (but note that oxycodone concentrate now available in UK)|
220.127.116.11 Mild pain (1–4 on a 0–10 scale): For patients with mild pain (<5/10), and those who are opioid-naïve, normal release tramadol is a reasonable choice of analgesic agent. Tramadol has 1/5th the potency of oral morphine and the starting dose is 50 mg 6 hourly prn or qid. Patients who respond but need qid dosing are best placed onto the bd sustained release form. Codeine can also be used but it is a pro-drug of morphine, and 10–15% of the population is unable to convert it into active morphine, leaving them with unacceptable toxicity (Lötsch & Geisslinger, 2006).
18.104.22.168 Moderate to severe chronic pain (>4/10): Patients with chronic moderate (5–6/10) or severe pain (>6/10) can be started on tramadol as above, but will usually need to go onto more potent opioids rapidly if they do not respond. Oxycodone has twice the potency of morphine and is associated with less drowsiness and hallucinations. For rapid onset, the normal release preparation can be used 4–6 hourly or qid, but most patients eventually prefer the convenience of the bd sustained release forms (Mucci-LoRusso et al, 1998).
Patches can be used to deliver either fentanyl or buprenorphine, both of which are very potent opioids. Fentanyl causes significantly less nausea, sedation and constipation compared to morphine (Clark et al, 2004). When given the choice of fentanyl patches or oral morphine for chronic pain, patients prefer the patches (Ahmedzai & Brooks, 1997). Buprenorphine often initially causes nausea but this can be covered by the use of an anti-emetic such as metoclopramide and is otherwise well tolerated. Note that there are two formulations of buprenorphine patch – the low doses (5–10 mcg/h) are primarily for use in arthritis or other non-cancer patients, whereas the higher doses (35 mcg/h and greater) are more useful for cancer pain.
When using normal release oral medication, the dose can be titrated up daily by 30–50% until pain is controlled or unacceptable side effects occur. With sustained release oral medication it is advisable to wait 2–3 d between dose increments. With patches, doses should not normally be increased at <3 d intervals.
With all sustained release analgesics, it is essential to offer the patient a normal release ‘rescue medication’ for breakthrough pain. This is particularly important when breakthrough pain occurs quickly and predictably, e.g. on weight-bearing with disease in the spine or legs. It is important to distinguish this kind of ‘incident pain’ from pain arising from end of dose failure with sustained release medications, or spontaneous pains associated with neuropathy or opioid-induced hyperalgesia (Davies et al, 2009). Normal release oxycodone or morphine can be used, at 1/6th of the current 24-h total opioid dose. However, often the absorption of these oral drugs can be too slow for some episodes of breakthrough pain. Fentanyl has a high bioavailability via the transmucosal route, which has led to the development of fast-acting (but short-lived) fentanyl formulations. These include fentanyl lozenges; buccal tablets; or sublingual tablets (Weinstein et al, 2009; Lennernäs et al, 2010). Nasal sprays are now also available. Normally, a patient should not need to use more 2–3 of these relatively expensive fentanyl formulations per day for breakthrough pain; if more are being taken, either the background medication needs to be increased or the patient should be referred to a specialist. There is no place for pethidine in the treatment of pain in myeloma.
22.214.171.124 Acute onset moderate-severe pain (>4/10): For patients with sudden onset of moderate to severe pain, e.g. after long bone fracture or vertebral collapse, the subcutaneous route is recommended, e.g. with oxycodone or morphine, until the pain is controlled and then a sustained release oral preparation can be started. Opioids can be combined with other drugs, e.g. an anti-emetic in the syringe driver. There is usually no advantage of using the intravenous route, except in acute severe pain and this should be administered by a pain or palliative medicine specialist. Patient controlled analgesia (PCA) pumps are also of little value in myeloma patients, except in some cases of very severe oropharyngeal mucositis.
For non-emergency situations, there is no advantage of using injections or subcutaneous syringe drivers, except when the patient is vomiting or otherwise unable to take oral medication.
Diamorphine is a pro-drug for morphine and apart from its greater water solubility, it has no advantages over morphine or oxycodone for injections.
126.96.36.199 Adverse effects of opioids: With all opioids, it is important to offer the patient a laxative and to keep checking for the development of constipation. Transdermal fentanyl and buprenorphine are associated with reduced incidence of constipation (Clark et al, 2004; Tassinari et al, 2009). It is not necessary to routinely prescribe an anti-emetic with opioids, except for the first week when starting buprenorphine.
Most opioids cause dose-related sedation; however, fentanyl and oxycodone are associated with reduced sedation compared to morphine (Ahmedzai & Brooks, 1997; Clark et al, 2004; Reid et al, 2006). Patients who experience intolerable sedation due to opioids (or other drugs, e.g. thalidomide) may be considered for a trial of a psychostimulant such as methylphenidate or modafanil; this should only be prescribed by a specialist in palliative medicine. (See sections 7.5 and 7.6)
Respiratory depression is uncommon in patients treated chronically with opioids as long as dose increments are made carefully as outlined above. With the initiation of opioids, it is common to see a reduction in respiratory rate; however, this is usually balanced by changes in tidal volume so that minute ventilation initially remains steady. Care needs to be taken in patients with chronic obstructive pulmonary disorder or obstructive sleep apnoea, in whom the respiratory depression can occur even with low doses of opioids. True respiratory depression caused by opioids is diagnosed by a reduction in oxygen saturation (SaO2 < 90%) or by arterial blood gases. If this occurs, naloxone can be given but care must be taken not to provoke a serious increase in pain. Advice on future opioid dosing should be sought from a specialist in pain or palliative medicine.
Recently, a condition known as opioid-induced hyperalgesia has been consistently identified in animal studies and has also been demonstrated to occur in human studies (Ballantyne & Mao, 2003). This condition is characterized by increasing reporting of pain in the presence of increasing opioid dosage. The pain can be localized to the original lesion but is often generalized to adjacent dermatomes. The skin in the affected area may show hyperalgesia (increased pain response on normal painful stimulus) or allodynia (pain felt even on light touch). This is thought to be caused by downstream intracellular signalling mechanisms from the activated opioid receptor and involves the induction of nitric oxide and the opening of N-Methyl-d-aspartate (NMDA) channels, which are responsible for maintaining chronic and neuropathic pain (Mao et al, 2002; Mao, 2008). The management of this condition should be left to specialists in pain or palliative medicine; it involves reduction in the opioid dosage along with the introduction of an NMDA channel blocker, such as ketamine or methadone.
For details on currently available opioids and their usual starting doses; dose equivalents for conversions; calculation of prn dosing, see (Twycross & Wilcock, 2008).