Prescribing drugs of dependence in general practice

Part C1 - Opioids - Chapter 3

Clinical pharmacology

Last revised: 19 Jun 2020

Mode of action

Opioids act as either pure or partial agonists on opioid receptors in the central and peripheral nervous system. There are three main types of opioid receptors: mu, kappa and delta (µ,κ and δ). Receptor affinity varies with individual opioids. Action at receptors produces the range of opioid effects including:2,77,78

  • analgesia (analgesic activity of most clinically used opioids is due to their agonist activity at the mu receptor)
  • respiratory depression
  • cough suppression
  • euphoria
  • sedation
  • decreased gastrointestinal motility (leading to constipation)
  • physical dependence.

Metabolism and duration of activity

The response to opioids depends on many factors.79,80 Variations in response related to age and gender, combined with the significant individual (genetic) differences in opioid effects seen clinically, mean that doses need to be titrated to effect for each patient.

Age

Age is a better determinant than weight for the amount of opioid an adult is likely to require for effective analgesia. This appears to be mainly due to differences in pharmacodynamics of brain penetration rather than systemic pharmacokinetic factors.81–83

Gender

Gender also plays a complex role. Potentially due to interaction between oestrogen and opioid receptors, some studies have shown that women report more severe pain than men with similar disease processes or in response to painful stimuli.84,85

Genetics

Genetic differences influence opioid pharmacokinetics (metabolising enzymes, transporters) and pharmacodynamics (receptors and signal transduction elements). These contribute to the large inter-patient variability to opioid therapy.86,87

Most medicines are metabolised by the hepatic cytochrome P450 enzyme system. Within this system, and most relevant to opioid analgesia, is the CYP2D6 enzyme, which has over 100 allelic variants.88 These polymorphisms influence the speed of opioid metabolism, including the production of active metabolites, and severity of pain:48,89

  • Ultrarapid metabolisers (ie carriers of the CYP2D6 gene duplication) have significantly higher levels of morphine and morphine metabolites after administration of codeine and tramadol, increasing their risk of respiratory depression and death.90–91
  • Poor metabolisers are likely to have more severe postoperative pain than those who have other variants.

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 oral and sublingual formulations are usually used.

Musculoskeletal pain

There is limited evidence regarding buprenorphine for CNCP due to a lack of high-quality randomised controlled trials (RCTs).101 However, transdermal buprenorphine for osteoarthritis has been shown to be effective and well tolerated, with analgesic effects similar to tramadol.102

Neuropathic pain

Case reports suggest that buprenorphine is effective in peripheral103,104 and central neuropathic pain in the clinical setting.105 However, large trials are lacking and currently there is not enough evidence to support or dispute efficacy of buprenorphine in any neuropathic pain condition.106

Addiction medicine

Buprenorphine is listed for use in ORT (as Section100 [S100]).

In practice

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.107

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.108 There is a ceiling effect for respiratory depression but not for analgesia.109 If buprenorphine-induced respiratory depression occurs it may be completely reversed with naloxone,107 although higher than usual doses and a longer duration infusion of naloxone are required.110

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.108

Buprenorphine binds strongly to the mu receptor site, but does not fully activate it.111 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.111

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 CYP2D6.96,112 Ultrarapid metabolisers have significantly higher levels of morphine and morphine metabolites after the same dose of codeine.91 Poor metabolisers do not produce any morphine or gain any analgesic effect.

Codeine is subject to misuse and dependence, and is the most common prescription opioid associated with fatal overdoses in Victoria.7 Rates of misuse average between 21% and 29%, and rates of dependence average between 8% and 12%.7

Musculoskeletal pain

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.113

In practice

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.114 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.114,115

Given the variability in response and risk of harm, use of codeine should be closely monitored.

In November 2011, the Therapeutic Goods Administration (TGA) decided to remove the registration of dextropropoxyphene in Australia.116 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.117 In combination with paracetamol, it also provides little benefit above paracetamol alone.118

In practice

Dextropropoxyphene has now been limited to authorised prescribers 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 painkillers
  • have considered the contraindications for the medicine outlined in the product information, and have explained these 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 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.119

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.119

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.3 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.

In practice

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.120,121 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.76

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.

In practice

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.122 But it also has a long and unpredictable half-life (mean of 22 hours; range 4–190 hours), which increases the risk of accumulation.123

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, some antiretroviral agents) may increase methadone metabolism, which lowers methadone blood levels and leads to potential reduced efficacy or even withdrawal.124 Use of P450 inhibitors (eg other antiretroviral agents, some selective serotonin reuptake inhibitors [SSRIs], grapefruit juice, antifungal agents) may lead to raised methadone levels, which increases risk  of adverse effects or overdose.124 Checking for drug interactions with methadone can be done online.

In practice

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 are typically used three to four times daily to manage persistent pain.73

Methadone use is usually confined to specialist pain medicine areas125 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.73


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.126 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.112 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.127,128

While the clinical significance is uncertain, morphine is the most immunosuppressive of the currently available opioids.129,130

There has been a decrease in morphine prescribing in Australia.3 Prescriptions are most prevalent among older Australians.

Musculoskeletal pain

The evidence for morphine in managing CNCP, including low back pain, is poor.101

Neuropathic pain

Strong opioids including morphine have weak Grading of Recommendations Assessment, Development and Evaluation (GRADE) recommendations for use and are recommended as third line mainly because of safety concerns.131

In practice

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.132,133

Paradoxically, in acute postoperative pain, the CYP2D6 genotype does not appear to influence oxycodone requirements.134 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.134–136

Oxycodone-related deaths are currently relatively low in Australia; they are not comparable to numbers reported in the US.3

Musculoskeletal pain

The evidence for oxycodone in the management of CNCP is poor.101

Neuropathic pain

Strong opioids including oxycodone have weak GRADE recommendations for use and are recommended as third line mainly because of safety concerns.131

In practice

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,137 but the risks of misuse and diversion still exist.

Note that St John’s wort (Hypericum perforatum) induces metabolism of oxycodone, significantly reducing its plasma concentrations and efficacy.138


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.139

When used parenterally, pethidine does not provide better analgesia than morphine, but does induce more nausea and vomiting than morphine.140


Tapentadol is a combined weak mu agonist and noradrenaline reuptake inhibitor (acting on descending pain inhibition pathways) with no active metabolites.143–145 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.146

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.147 However, as it is metabolised by the liver, impaired hepatic function may require dose adjustment.148

Despite widespread use over several years in the US and Europe, there are only two reported cases of an overdose death.149 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.150,151 There are limited data to support a role for tapentadol in cancer pain.152

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.145,158

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.159 Hence, patients who are poor metabolisers receive less analgesic effect from tramadol.160

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.161,162 However, tramadol has less effect on gastrointestinal motor function than morphine.162,163 It causes less respiratory depression than other opioids at equianalgesic doses.164,165 Tramadol does not increase the incidence of seizures compared with other analgesic agents,166,167 although there is a risk of inducing serotonin toxicity when tramadol is combined with other serotonergic medicines, in particular SSRIs.168

Tramadol has a lower potential for misuse than conventional opioids.169

Musculoskeletal pain

There is fair evidence for tramadol in managing osteoarthritis.101

Neuropathic pain

Tramadol has a weak GRADE recommendation for use in neuropathic pain,131 and is regarded as generally second line due to tolerability and safety.131,170

In practice

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.

 

Formulations

The practical usefulness of opioids is related to the available formulations (Table 9).

Approximate equivalence doses

Oral morphine is the standard that other opioids are measured against. Full opioid agonists given in equianalgesic doses produce the same analgesic effect.172 However, accurate determination of equianalgesic doses is difficult due to individual variability in pharmacokinetics and dynamics.173

There are several published tables providing approximate equianalgesic doses. These are typically based on singledose studies in opioid-naïve subjects and may not be as relevant when conversions are made after repeated doses of an opioid.76 They also do not take into account incomplete cross-tolerance and patient-specific factors.125

Converting to methadone requires special caution. Regardless of how much other opioid the patient is being prescribed, commence methadone at low doses in accordance with the National guidelines for medicationassisted treatment for opioid dependence or in consultation with pain or addiction specialists.

Box 4. Useful tools for calculating equivalent doses

Opioid ceiling doses

Use caution when prescribing opioids at any dosage. Many harms are dose related, so aim for the lowest effective dose then carefully reassess for evidence of individual benefits and risks, especially when increasing dosage to 50 mg oral morphine equivalent (OME) or more per day. GPs must be able to justify a decision to titrate dosage to 100 mg or more OME per day and should avoid increasing dosage to 100 mg or more OME per day without specialist involvement.15 Higher opioid doses may be acceptable in cancer-related pain.

Tolerance is a predictable state of adaption where exposure to a drug induces changes that result in reduction of one or more of the drug’s effects over time.175 The patient becomes ‘desensitised’ to the drug and increased doses are then needed to get the same effect.

The decrease in the effectiveness of opioid analgesia has traditionally been attributed to opioid tolerance (a desensitisation of anti-nociceptive pathways to opioids).76 However, it is now known that administration of opioids can also result in opioid-induced hyperalgesia (OIH), which is at sensitisation of pro-nociceptive pathways leading to pain hypersensitivity. Both tolerance and OIH can significantly reduce the analgesic effect of opioids.176,177

The predictable and physiological decrease in the effect of a drug over time may be referred to as ‘pharmacological tolerance’. ‘Apparent tolerance’ occurs when both tolerance and OIH contribute to a decrease in the effectiveness of opioids.178,179

Opioids appear to differ in both the ability to induce tolerance and the degree of OIH. For example, methadone and fentanyl are less likely to lose effect over time as they promote opioid receptor internalisation, which results in receptor recycling. In contrast, the activation of opioid receptors by morphine leads to little or no receptor internalisation and thereby increased risk of development of tolerance.179–181

There is some evidence that administration of ‘commonly used’ dosages of oral opioids does not result in abnormal pain sensitivity.182

In an individual patient displaying decreased effectiveness of opioid therapy, it can be impossible to determine whether tolerance or OIH is causing a reduction in pain control, creating a management dilemma: inadequate pain relief due to tolerance may improve with opioid dose escalation, while improvements in analgesia in the presence of OIH may follow a reduction in opioid dose.178 The only reasonable action in these circumstances is to reduce opioid doses.

Tolerance also occurs to some of the adverse effects of opioids. Rapid tolerance may develop to sedation, cognitive effects, nausea and respiratory depression, but there is little change in miosis or constipation.178

‘Dependence’ has historically been defined in pharmacological terms: a time-limited state that develops during chronic drug treatment in which cessation elicits an abstinence reaction (withdrawal) and is reversed by renewed administration of the drug.77

Opioid withdrawal syndrome is characterised by signs and symptoms of sympathetic stimulation due to decreased sympathetic antagonism by opioids (Table 11).77 Symptoms start two to three half-lives after the last dose of opioid. For example, oxycodone has a half-life of 3–4 hours: symptoms would start after 6–12 hours, peak at approximately 48–72 hours, and resolve within 7–14 days.77 Timelines and symptoms vary depending on the duration of action,65 specific dose, speed of taper, and duration of use.77

Withdrawal can be minimised by gradual reduction of opioid use. Where it does occur, unless a patient has significant comorbidity or is otherwise medically unstable, withdrawal is not life threatening, although it may be very distressing.65,77 Acute withdrawal (when opioids are stopped suddenly, or an antagonist such as naloxone or naltrexone is administered) should be treated by reintroducing opioids or by IV fluids, glucose, and adrenergicblocking drugs. Clonidine is useful in this situation.77 Reassurance and comfort measures may also be required.77

Adverse effects

Common opioid-related adverse effects are sedation, pruritus, nausea, vomiting, slowing of gastrointestinal function and urinary retention.183–185 Uncommonly, opioids (methadone, oxycodone) are associated with prolonged QT-interval with a risk of TdP and cardiac arrest.186,187 These effects are dose related.

 

Other harms

Refer to Treatment seeking for pharmaceutical opioids

Refer to Hospitalisation due to opioids

Refer to Overdose and mortality

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