Presented in alphabetical order
Buprenorphine is a partial agonist at mu opioid receptors and an antagonist at delta and kappa receptors. It is typically used for analgesia (in low-dose patch formulation) and in ORT, where sublingual formulations are usually used.
There is limited evidence regarding buprenorphine for CNCP due to a lack of high-quality RCTs.303 However, transdermal buprenorphine for osteoarthritis has been shown to be effective and well tolerated, with analgesic effects similar to tramadol.304
Case reports suggest that buprenorphine is effective in peripheral315,316 and central neuropathic pain in the clinical setting.317 However, large trials are lacking and currently there is not enough evidence to support or dispute efficacy of buprenorphine in any neuropathic pain condition.318
Buprenorphine is listed for use in ORT (as Section100 [S100]).
Buprenorphine is PBS listed for chronic severe pain and ORT.
Transdermal patches (used for pain, not ORT) generally provide a week of analgesia. Occasionally, patients complain that there is release of the drug from the transdermal patch for only six, or rarely five, days. In these instances, the patches may need to be changed more frequently than weekly.
Buprenorphine can be safely used in patients with renal impairment and has less immunosuppressive effect than pure mu-opioid agonists.319
As long as sedative medication is not given concurrently, the risk of respiratory depression with buprenorphine is low compared to morphine, methadone, hydromorphone and fentanyl.320 There is a ceiling effect for respiratory depression but not for analgesia.321 If buprenorphine-induced respiratory depression occurs it may be completely reversed with naloxone,319 although higher than usual doses and a longer duration infusion of naloxone are required.322
Withdrawal symptoms may occur if buprenorphine is ceased after long-term treatment; however, these symptoms are milder and more delayed in onset (≥72 hours) compared with other opioids.320
Buprenorphine binds strongly to the mu receptor site, but does not fully activate it.323 Therefore, if buprenorphine is combined with pure mu agonists (eg morphine, fentanyl), interactions may occur. For example, if a pure mu agonist is given to a person on maintenance buprenorphine it may be less effective. Conversely, buprenorphine could theoretically cause a withdrawal reaction if given to a patient taking longer-term opioid (mu) therapy.323
Antagonism of response to pure mu agonists (precipitated withdrawal) can occur with buprenorphine but it has only been demonstrated at buprenorphine doses exceeding the ranges used for analgesia (eg at dosages for ORT). In practice, these drug interactions are unlikely.
Codeine is a weak mu receptor agonist (200-fold weaker affinity than morphine) and its analgesic action depends on the metabolism of about 10% of the dose to morphine, via CYP2D6.324,325 Ultrarapid metabolisers have significantly higher levels of morphine and morphine metabolites after the same dose of codeine.326 Poor metabolisers do not produce any morphine or gain any analgesic effect.
Codeine is subject to misuse and dependence, and is the commonest prescription opioid associated with fatal overdoses in Victoria.327 Rates of misuse average between 21% and 29%, and dependence average between 8% and 12%.327
Codeine is commonly used in combination with other minor analgesics (eg paracetamol, ibuprofen). There is highquality evidence that combination codeine medicines provide clinically important pain relief in the immediate term, but this is mostly in acute pain.16
Codeine is classified as a weak opioid. It is listed by the PBS for mild to moderate pain. There is no role for codeine in chronic pain.
A single 60 mg dose provides good analgesia to few adults: 12 patients need to be treated for one to achieve a 50% reduction in postoperative pain.328 OTC preparations containing low doses of 8–15 mg codeine phosphate are considered sub-therapeutic.
Combining codeine with non-opioid analgesics provides limited additional analgesic benefit: seven patients need to be treated with ibuprofen 400 mg/codeine 25.6–60 mg for one to obtain at least a 50% reduction in postoperative pain when compared to treatment with ibuprofen 400 mg alone.328,329
Given the variability in response and risk of harm, use of codeine should be closely monitored.
In November 2011, the TGA decided to remove the registration of dextropropoxyphene in Australia.330 It was withdrawn from the Food and Drug Administration (FDA) in the US due to risks of QT-interval prolongation and possibility of Torsades de Pointes (TdP) and cardiogenic death.
Oral dextropropoxyphene alone is a poorly effective analgesic.331 In combination with paracetamol, it also provides little benefit above paracetamol alone.332
Dextropropoxyphene has now been limited to authorised users for previous users only. To prescribe this medication, GPs need to:
- be aware that the medicine is only approved for use in patients not able to be adequately treated with other mild pain killers
- have considered the contraindications for the medicine outlined in the product information and have explained them to the patient at the time of prescribing
- have considered any recent changes to the patient’s clinical presentation or biochemical status
- have warned the patient at the time of prescribing about appropriate use of the medicine
- be satisfied at the time of prescribing that the patient’s history does not indicate that the patient is at risk of accidental or intentional self-harm.
The conditions also require that a signed Prescriber Confirmation form is presented to the pharmacist dispensing these medicines before supplying them to the patient every time a patient presents for a prescription.
Fentanyl is a highly potent opioid, which is active at the mu receptor. It is metabolised almost exclusively in the liver to minimally active metabolites. This makes it particularly useful in renal failure: <10% of unmetabolised fentanyl is renally excreted.333
It is available as transdermal patches, oral transmucosal lozenges or lollipops and injectable preparations. The transdermal system offers an excellent option for long-term treatment of cancer pain, but the RACGP believes it is not suitable for CNCP. A 25 ug/hour fentanyl patch is equivalent to approximately 90 mg of oral morphine per day. Oral transmucosal fentanyl rapidly achieves high plasma concentrations and is indicated to treat breakthrough pain in cancer patients who are not opioid naïve.333
Fentanyl-related mortality is currently relatively low in Australia compared to the US and parts of Europe. However, fentanyl misuse is on the rise in Australia with a large proportion of these deaths occurring among at-risk groups who inject drugs.334 Because of the misuse potential, this drug should be used only as indicated. It has known diversional potential, extremely high street value and risk of misuse.
Fentanyl is PBS listed for severe disabling pain and is usually used in cancer care or in acute hospital settings.
In the opioid-naïve patient, there is a significant risk of toxicity and overdose. Fentanyl patches are not suitable to be used as the initial agent in the management of pain for opioid-naïve patients due to high morphine-equivalent doses. Fentanyl should only be used in the case of cancer pain when all other options have been exhausted.
Be aware that local heat (eg hydrotherapy pool) may increase absorption from the patch.
Hydromorphone is an effective strong opioid acting as a mu receptor agonist. It is approximately five times as potent as morphine and provides slightly better clinical analgesia than morphine, but has similar adverse effects.335,336 The main metabolite of hydromorphone is hydromorphone-3-glucuronide (H3G), which is dependent on the kidneys for excretion, has no analgesic action and can lead to dose-dependent neurotoxic effects.337
It is available as solution for injection, oral liquid and tablets. It also has extremely high potential for misuse and high street value for those who divert this drug.
Hydromorphone is PBS listed for severe disabling pain, but in practice is usually restricted to malignant pain, or patients undergoing dialysis. It is not suitable to be used as the initial agent in the management of pain for opioidnaïve patients.
Methadone is a synthetic opioid acting as an agonist at the mu receptor with additional ketamine-like antagonism at the N-methyl-D-aspartate receptor. It is commonly used for the maintenance treatment of patients with an addiction to opioids and in patients with chronic pain.
It has good oral bioavailability (70–80%), high potency, a long duration of action and no active metabolites.338 But it also has a long and unpredictable half-life (mean of 22 hours; range 4–190 hours), which increases the risk of accumulation.339
Concurrent administration of other drugs that are metabolised by the P450 enzyme system may have significant effects. P450 inducers (eg carbamazepine, rifampicin, phenytoin, St John’s wort (Hypericum perforatum), some antiretroviral agents) may increase methadone metabolism, which lowers methadone blood levels and leads to potential reduced efficacy or even withdrawal.340 Use of P450 inhibitors (eg other antiretroviral agents, some SSRIs, grapefruit juice, antifungal agents) may lead to raised methadone levels, which increases risk of adverse effects or overdose.340 Checking for drug interactions with methadone can be done online.
Methadone is PBS listed for severe disabling pain and for ORT (as S100). Two formulations are available in Australia. Methadone liquid is used once daily for maintenance in opioid dependent patients. Methadone tablets may be used two to four times daily to manage persistent pain.341
Methadone use is usually confined to specialist pain medicine areas342 as it has complicated and unpredictable pharmacokinetics. Extreme caution must be taken when inducting a person onto an appropriate dose of methadone, with a slow titration regimen and close monitoring required. It may take up to two weeks to reach steady state levels, and drug accumulation may cause excessive sedation and high risk of overdose and death if the dose is increased rapidly.341
Morphine has been the most widely used opioid in acute, persistent and cancer pain, and remains the standard against which other opioids are compared.
The main metabolites of morphine (primarily formed by hepatic glucuronidation) are morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). M6G is a mu opioid receptor agonist and is the main mediator of analgesia.343 M3G has very low affinity for opioid receptors and no analgesic activity, but may be responsible for the neurotoxic symptoms such as hyperalgesia, allodynia and myoclonus, sometimes associated with high doses of morphine.325 Both metabolites are renally eliminated.
Higher doses, older age, impaired renal function and the oral administration (due to first-pass metabolism) are associated with higher M3G and M6G concentrations and therefore with the potential risk of severe long-lasting sedation and respiratory depression.344,345
While the clinical significance is uncertain, morphine is the most immunosuppressive of the currently available opioids.346,347
There has been a decrease in morphine prescribing in Australia.334 Prescriptions are most prevalent among older Australians.
The evidence for morphine in managing CNCP, including low back pain, is poor.303
Strong opioids including morphine have weak GRADE recommendations for use and are recommended as third line mainly because of safety concerns.96
Morphine formulations are indicated by the PBS for severe disabling pain (cancer, palliative care) and chronic severe pain. Commencement doses vary according to patient selection and age.
Oxycodone action appears to be mediated primarily by mu receptor agonism. Oxycodone contributes the majority of drug effect, as its metabolites, noroxycodone and oxymorphone (via CYP3A4), are only weakly active. However, oxycodone concentration may be dependent on CYP2D6 activity, resulting in ultrarapid metabolisers experiencing better analgesic effects than poor metabolisers, but also higher toxicity.348,349
Paradoxically, in acute postoperative pain, the CYP2D6 genotype does not appear to influence oxycodone requirements.350 There is an increasing use of oxycodone in the acute, hospital and perioperative settings as it has a faster onset of action than morphine, better oral bioavailability, longer duration of action, fewer concerns about metabolites and lower rate of adverse effects based on these pharmacological properties.350–352
Oxycodone-related deaths are currently relatively low in Australia; they are not comparable to numbers reported in the US.334
The evidence for oxycodone in the management of CNCP is poor.303
Strong opioids including oxycodone have weak GRADE recommendations for use and are recommended as third line mainly because of safety concerns.96
Oxycodone is PBS listed for severe disabling pain and chronic severe pain. It is particularly popular in hospital and acute pain settings. Care should be used in rehabilitation settings to minimise chronic use.
Care should also be taken by GPs continuing to prescribe oxycodone in the community post discharge from the hospital setting. All patients should have plans to be weaned off their opioid analgesics post discharge.
The use of oxycodone is increasing rapidly and addiction specialists report that it is often a drug of choice for misuse. A combination of oxycodone with naloxone has recently been released in Australia. This combination substantially reduces the chance of constipation,353 but the risks of misuse and diversion still exist.
Note that St John’s wort (H. perforatum) induces metabolism of oxycodone, significantly reducing its plasma concentrations and efficacy.354
Pethidine is a synthetic opioid active at the mu receptor. IM pethidine has been widely used in Australia for a range of pain problems. Its use is decreasing because of multiple disadvantages compared to other opioids. Repeated dosing or renal failure leads to accumulation of its active metabolite (norpethidine), which is associated with neuroexcitatory effects that range from nervousness to tremors, twitches, multifocal myoclonus and seizures.355
When used parenterally, pethidine does not provide better analgesia than morphine, but does induce more nausea and vomiting than morphine.356
Use of pethidine is discouraged in favour of other opioids.357,358
It has high addiction potential and is not recommended for the treatment of persistent pain.
Pethidine is no longer indicated for the treatment of migraines.
Tapentadol is a combined weak mu agonist and noradrenaline reuptake inhibitor (acting on descending pain inhibition pathways) with no active metabolites.359–361 In a number of chronic pain conditions, tapentadol shows efficacy that is comparable or better than conventional opioids but with reduced rates of gastrointestinal adverse effects (eg nausea, vomiting, constipation), which results in less treatment discontinuation.362
At doses up to the maximum recommended 500 mg/day, tapentadol has no effect on heart rate or blood pressure due to noradrenaline reuptake inhibition, even in patients with hypertension and/or on antihypertensives.363 However, as it is metabolised by the liver, impaired hepatic function may require dose adjustment.364
Despite widespread use over several years in the US and Europe, there are only two reported cases of an overdose death.365 Although it is a controlled medicine in all countries, tapentadol shows a lower rate of misuse and diversion than oxycodone and hydrocodone and a rate comparable to tramadol.366,367 There are limited data to support a role for tapentadol in cancer pain.368
Currently, relatively few RCTs have studied tapentadol. There is evidence of benefit in osteoarthritis, low back pain and postoperative pain.305,369–371 Three randomised trials studying tapentadol for managing chronic pain of osteoarthritis and low back found that 32% of patients received greater than 50% pain relief.303
Due to effect of noradrenaline uptake inhibition on descending pathways of pain, tapentadol modulates increased conditioned pain seen with neuropathic pain.372 This effect has been confirmed in diabetic neuropathy.360
Tapentadol is PBS listed for chronic severe pain.
Start at low dose 50 mg and titrate the dose according to response increase: every three days, increase the dose by 50 mg for each twice-daily dose until adequate analgesia or the 50 mg OME dose of 125 mg/day is reached.
Tramadol acts as both a weak opioid agonist and as a serotonin and noradrenaline reuptake inhibitor. Due to the combined effects, it is commonly referred to as an atypical centrally acting analgesic.361,373
Tramadol is metabolised by CYP2D6 to an active metabolite, O-desmethyltramadol (M1), which is a more potent mu opioid receptor agonist than the parent drug.374 Hence, patients who are poor metabolisers receive less analgesic effect from tramadol.375
The adverse-effect profile of tramadol is different from other opioids. The most common side effects are nausea and vomiting, which occur at rates similar to morphine.376,377 However, tramadol has less effect on gastrointestinal motor function than morphine.377,378 It causes less respiratory depression than other opioids at equianalgesic doses.379,380 Tramadol does not increase the incidence of seizures compared with other analgesic agents,381,382 although there is a risk of inducing serotonin toxicity when tramadol is combined with other serotonergic medicines, in particular SSRIs.383
Tramadol has a lower potential for misuse than conventional opioids.384
There is fair evidence for tramadol in managing osteoarthritis.303
Tramadol has a weak GRADE recommendation for use in neuropathic pain,96 and is regarded as generally second line because due to tolerability and safety.96,385
Tramadol is listed on the PBS for acute or chronic pain not responding to aspirin and/or paracetamol; short-term treatment of acute pain.
Side effects often limit use, but tramadol can be useful if tolerated.