Prescribing drugs of dependence in general practice

Part C1 - Opioids - Chapter 3

Clinical pharmacology

Part C1 - Opioids
    5. Clinical pharmacology
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Last revised: 10 Jan 2022

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.

The TGA-approved indications for all opioids changed in 2020.

Indications were aligned across class and divided into immediate-release and modified-release categories, with the exception of fentanyl patches, which have a separate indication.

Prescribers are advised to familiarise themselves with the new indications across the class.

The indication for immediate release products is:

  • [Product] is indicated for the short-term management of severe pain for which other treatment options have failed, are contraindicated, not tolerated or are otherwise inappropriate to provide sufficient management of pain.

The indication for modified release products is:

  • [Product] is indicated for the management of severe pain where:
    • other treatment options have failed, are contraindicated, not tolerated or are otherwise inappropriate to provide sufficient management of pain, and
    • the pain is opioid-responsive, and
    • requires daily, continuous, long-term treatment
  • [Product] is not indicated for use in chronic non-cancer pain other than in exceptional circumstances.
  • [Product] is not indicated as an as-needed (PRN) analgesia.
  • Not for use in opioid-naïve patients (hydromorphone and fentanyl patches only).

The TGA has deliberately not defined ‘exceptional circumstances’, as it is acknowledged there may be a range of potential situations where they might apply to an individual patient, subject to the clinical judgement of the prescriber. However, the overall outcome of the indication change is to narrow the general circumstances in which opioids are prescribed for chronic non-cancer pain and for prescribers to rule out other potential treatment modalities before determining that exceptional circumstances apply. In exceptional circumstances, if other treatment options fail, have limited benefit or are inappropriate, supervised opioid treatment may remain an acceptable long-term therapeutic option.

The indication for fentanyl patches is:

  • For the management of pain associated with cancer, palliative care, and other conditions in opioid-tolerant patients where:
    • other treatment options have failed, are contraindicated, not tolerated or are otherwise inappropriate to provide sufficient management of pain, and
    • the pain is opioid-responsive, and
    • severe enough to require daily, continuous, long term opioid treatment
  • Not for use in opioid-naïve patients.

On 1 June 2020, PBS opioid listings were amended to align with the revised product indications above. General information on these changes, as well as changes to authority requirements, is detailed in ‘Section 2.2.2 Pharmaceutical Benefits Scheme requirements for opioid prescriptions’; however, you should check the PBS listing for the individual product you contemplate prescribing to confirm the clinical criteria and prescribing requirements.

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 severe 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 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 chronic, 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 chronic, 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 chronic, 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, severe pain not responding to aspirin and/or paracetamol and for the short-term treatment of acute, severe 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

  1. Berterame S, Erthal J, Thomas J, et al. Use of and barriers to access to opioid analgesics: A worldwide, regional, and national study. Lancet 2016;387(10028):1644–56.
  2. The Pharmaceutical Benefits Scheme (PBS) Drug Utilisation Sub-committee (DUSC). Opioid analgesics: Overview. Canberra: Department of Health, 2014. Available at www. [Accessed 11 July 2017].
  3. Roxburgh A, Ritter A, Slade T, Burns L. Trends in drug use and related harms in Australia, 2001 to 2013. Sydney: National Drug and Alcohol Research Centre, University of New South Wales, 2013.
  4. Degenhardt L, Gisev N, Cama E, et al. The extent and correlates of community-based pharmaceutical opioid utilisation in Australia. Pharmacoepidemiol Drug Saf 2016;25(5):521–38.
  5. Therapeutic Goods Administration. Update on the proposal for the rescheduling of codeine products: Codeine containing medicines to move to prescription only. Canberra: TGA, 2016 [Accessed 20 December 2016].
  6. Rogers KD, Kemp A, McLachlan AJ, Blyth F. Adverse selection? A multi-dimensional profile of people dispensed opioid analgesics for persistent non-cancer pain. PLoS One 2013;8(12):e80095.
  7. Vowles KE, McEntee ML, Julnes PS, et al. Rates of opioid misuse, abuse, and addiction in chronic pain: A systematic review and data synthesis. Pain 2015;156(4):569–76.
  8. Fleming MF, Balousek SL, Klessig CL, Mundt MP, Brown DD. Substance use disorders in a primary care sample receiving daily opioid therapy. J Pain 2007;8(7):573–82.
  9. Chou R, Deyo R, Devine E, et al. The effectiveness and risks of long-term opioid treatment of chronic pain. Rockville, MD: Agency for Healthcare Research and Quality, 2014 ehc/products/557/1971/chronic-pain-opioid-treatmentreport-141007.pdf [Accessed 11 July 2017].
  10. Chou R, Turner JA, Devine EB, et al. The effectiveness and risks of long-term opioid therapy for chronic pain: A systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med 2015;162(4):276–86.
  11. Nielsen S, Bruno R, Degenhardt L, et al. The sources of pharmaceuticals for problematic users of benzodiazepines and prescription opioids. Med J Aust 2013;199(10):696–69.
  12. Australian Institute of Health and Welfare. National hospital morbidity database (NHMD). Canberra: AIHW, 2017 [Accessed 4 September 2017].
  13. Pennington Institute. Australia’s annual overdose report. Melbourne: Pennington Institute, 2016. Available at www. [Accessed 11 July 2017].
  14. Gomes T, Mamdani MM, Dhalla IA, Paterson JM, Juurlink DN. Opioid dose and drug-related mortality in patients with nonmalignant pain. Arch Intern Med 2011;171(7):686–91.
  15. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain – United States, 2016. JAMA 2016;315(15):1624–45.
  16. Paulozzi L, Mack K, Jone C. Vital signs: Risk for overdose from methadone used for pain relief — United States, 1999–2010. Atlanta, GA: Centers for Disease Control and Prevention, 2012 mmwrhtml/mm6126a5.htm [Accessed 11 July 2017].
  17. Paulozzi LJ, Xi Y. Recent changes in drug poisoning mortality in the United States by urban–rural status and by drug type. Pharmacoepidemiol Drug Saf 2008;17(10):997–1005.
  18. Coroners Court of Victoria. Submission to the Inquiry into Drug Law Reform: Coronial recommendations on drug harm reduction. Melbourne: Coroners Court of Victoria, 2017.
  19. Sproule B. Prescription monitoring programs in Canada: Best practice and program review. Ottawa, ON: Canadian Centre on Substance Abuse, 2015 Resource Library/CCSA-Prescription-Monitoring-Programs-inCanada-Report-2015-en.pdf [Accessed 29 September 2016].
  20. Brady JE, Wunsch H, DiMaggio C, et al. Prescription drug monitoring and dispensing of prescription opioids. Public Health Rep 2014;129(2):139–47.
  21. Paulozzi LJ, Kilbourne EM, Desai HA. Prescription drug monitoring programs and death rates from drug overdose. Pain Med 2011;12(5):747–54.
  22. Li G, Brady JE, Lang BH, et al. Prescription drug monitoring and drug overdose mortality. Injury Epidemiology 2014;1(1):1–8.
  23. Goodin A, Blumenschein K, Freeman PR, Talbert J. Consumer/patient encounters with prescription drug monitoring programs: Evidence from a Medicaid population. Pain Physician 2012;15(3 Suppl):ES169–75.
  24. Islam MM, McRae IS. An inevitable wave of prescription drug monitoring programs in the context of prescription opioids: Pros, cons and tensions. BMC Pharmacol Toxicol 2014;15:46.
  25. Clark T, Eadie J, Knue P, Kreiner P, Strickler G. Prescription drug monitoring programs: An assessment of the evidence for best practices: The Prescription Drug Monitoring Program Center of Excellence, 2012.
  26. Ogeil RP, Heilbronn C, Lloyd B, Lubman DI. Prescription drug monitoring in Australia: Capacity and coverage issues. Med J Aust 2016;204(4):148.
  27. Sabanovic H, Harris B, Clavisi O, Bywaters L. Attitudes towards opioids among patients prescribed medication in Victoria. Melbourne: Move Muscle, Bone & Joint Health, 2016 MOVE-Opioid-study.aspx [Accessed 19 February 2017].
  28. Harris S, Taylor S, National Treatment Agency. Clinical governance in drug treatment: A good practice guide for providers and commissioners. London: NHS National Treatment Agency for Substance Misuse, 2009 [Accessed 11 July 2017].
  29. Chewning B, Bylund CL, Shah B, et al. Patient preferences for shared decisions: A systematic review. Patient Educ Couns 2012;86(1):9–18.
  30. The Royal Australian College of General Practitioners. Standards for general practices. 4th edn. Melbourne: RACGP, 2013.
  31. Coulter A, Collins A. Making shared decision-making a reality: No decision about me, without me. London: The King’s Fund, 2011.
  32. O’Shea E. Quality in Practice Committee: Communicating risk to patients. Dublin: Irish College of General Practitioners, 2014.
  33. Hoffmann TC, Montori VM, Del Mar C. The connection between evidence-based medicine and shared decision making. JAMA 2014;312(13):1295–96.
  34. Stacey D, Bennett CL, Barry MJ, et al. Decision aids for people facing health treatment or screening decisions. Cochrane Database Syst Rev 2011(10):CD001431.
  35. Hoffmann TC, Legare F, Simmons MB, et al. Shared decision making: What do clinicians need to know and why should they bother? Med J Aust 2014;201(1):35–39.
  36. Ahmed H, Naik G, Willoughby H, Edwards AG. Communicating risk. BMJ 2012;344:e3996.
  37. Patient Safety and Quality Improvement Service. Guide to informed decision-making in healthcare. Brisbane: Queensland Health, 2012.
  38. Clayman ML, Bylund CL, Chewning B, Makoul G. The impact of patient participation in health decisions within medical encounters: A systematic review. Med Decis Making 2016;36(4):427–52.
  39. Shay LA, Lafata JE. Where is the evidence? A systematic review of shared decision making and patient outcomes. Med Decis Making 2015;35(1):114–31.
  40. Thompson-Leduc P, Clayman ML, Turcotte S, Legare F. Shared decision-making behaviours in health professionals: A systematic review of studies based on the Theory of Planned Behaviour. Health Expect 2015;18(5):754-74.
  41. Legare F, Stacey D, Turcotte S, et al. Interventions for improving the adoption of shared decision making by healthcare professionals. Cochrane Database Syst Rev 2014;9:Cd006732.
  42. Hoffmann TC, Del Mar C. Patients’ expectations of the benefits and harms of treatments, screening, and tests: A systematic review. JAMA Intern Med 2015;175(2):274–86.
  43. Frei M. Opioid dependence: Management in general practice. Aust Fam Physician 2010;39(8):548–52.
  44. National Institute on Drug Abuse. Prescription drugs: Abuse and addiction. Rev edn. Bethesda, MD: NIDA, 2011.
  45. Gowing L, Ali R, Dunlop A, Farrell M, Lintzeris N. National guidelines for medication-assisted treatment of opioid dependence. Canberra: Commonwealth of Australia, 2014 CA257CD1001E0E5D/$File/National_Guidelines_2014.pdf [Accessed 11 July 2017].
  46. Heit H, Lipman A. Pain: Substance abuse issue in the treatment of pain. In: Moore R, editor. Biobehavioral approaches to pain. New York: Springer Science+Business Media, LLC, 2009.
  47. Arizona Department of Health Services. Arizona opioid prescribing guidelines: A voluntary, consensus set of guidelines that promotes best practices for prescribing opioids for acute and chronic pain. Phoenix, AZ: Arizona Department of Health, 2014. Available at http://azdhs. gov/documents/audiences/clinicians/clinical-guidelinesrecommendations/prescribing-guidelines/az-opiodprescribing-guidelines.pdf [Accessed 11 July 2017].
  48. Schug SA, Palmer GM, Scott DA, Halliwell R, Trinca J, editors. Acute pain management: Scientific evidence. 4th edn. Melbourne: Australia and New Zealand College of Anaesthetists and Faculty of Pain Medicine, 2015 [Accessed 11 July 2017].
  49. Sehgal N, Manchikanti L, Smith HS. Prescription opioid abuse in chronic pain: A review of opioid abuse predictors and strategies to curb opioid abuse. Pain Physician 2012;15(3 Suppl):ES67–92.
  50. Gordon A, Cone EJ, DePriest AZ, Axford-Gatley RA, Passik SD. Prescribing opioids for chronic noncancer pain in primary care: Risk assessment. Postgrad Med 2014;126(5):159–66.
  51. Deyo RA, Von Korff M, Duhrkoop D. Opioids for low back pain. BMJ 2015;350:g6380.
  52. Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. Recommendations regarding the use of opioid analgesics in patients with chronic noncancer pain. Melbourne: ANZCA and FPM, 2015 [Accessed 11 July 2017].
  53. Australian and New Zealand College of Anaesthetists. Guidelines on acute pain management. Melbourne: ANZCA, 2013 Documents/ps41-2013-guidelines-on-acute-painmanagement [Accessed 11 July 2017].
  54. Hughes MA, Biggs JJ, Theise MS, et al. Recommended opioid prescribing practices for use in chronic non-malignant pain: A systematic review of treatment guidelines. J Manag Care Med 2011;14(3):52.
  55. Kahan M, Mailis-Gagnon A, Wilson L, Srivastava A, National Opioid Use Guideline Group. Canadian guideline for safe and effective use of opioids for chronic noncancer pain: Clinical summary for family physicians. Part 1: general population. Can Fam Physician 2011;57(11):1257-66, e407–18.
  56. Drug and Alcohol Services South Australia. Opioid prescription in chronic pain conditions. Adelaide: DAAS SA, Flinders Medical Centre Pain Management Unit, Royal Adelaide Hospital Pain Management Unit, 2008.
  57. Huxtable CA, Roberts LJ, Somogyi AA, MacIntyre PE. Acute pain management in opioid-tolerant patients: A growing challenge. Anaesth Intensive Care 2011;39(5):804–23.
  58. Quinlan J, Carter K. Acute pain management in patients with persistent pain. Curr Opin Support Palliat Care 2012;6(2):188–93.
  59. Schug SA. Acute pain management in the opioid-tolerant patient. Pain Manag 2012;2(6):581–91.
  60. Lyapustina T, Castillo R, Omaki E, et al. The contribution of the emergency department to opioid pain reliever misuse and diversion: A critical review. Pain Pract 2017. doi: 10.1111/ papr.12568.
  61. Barnett ML, Olenski AR, Jena AB. Opioid-prescribing patterns of emergency physicians and risk of long-term use. N Engl J Med 2017;376(7):663–73.
  62. Macintyre PE, Huxtable CA, Flint SL, Dobbin MD. Costs and consequences: A review of discharge opioid prescribing for ongoing management of acute pain. Anaesth Intensive Care 2014;42(5):558–74.
  63. Tanabe P, Paice JA, Stancati J, Fleming M. How do emergency department patients store and dispose of opioids after discharge? A pilot study. J Emerg Nurs 2012;38(3):273–79.
  64. Lewis ET, Cucciare MA, Trafton JA. What do patients do with unused opioid medications? Clin J Pain 2014;30(8):654–62.
  65. Thorson D, Biewen P, Bonte B, et al. Acute pain assessment and opioid prescribing protocol. Bloomington, MN: Institute for Clinical Systems Improvement, 2014 [Accessed 11 July 2017].
  66. Harris K, Curtis J, Larsen B, et al. Opioid pain medication use after dermatologic surgery: A prospective observational study of 212 dermatologic surgery patients. JAMA Dermatol 2013;149(3):317–21.
  67. Bates C, Laciak R, Southwick A, Bishoff J. Overprescription of postoperative narcotics: A look at postoperative pain medication delivery, consumption and disposal in urological practice. J Urol 2011;185(2):551–55.
  68. Rodgers J, Cunningham K, Fitzgerald K, Finnerty E. Opioid consumption following outpatient upper extremity surgery. J Hand Surg Am 2012;37(4):645–50.
  69. Platis A, Wenzel T. Hospital oxycodone utilisation research study (HOURS). Adelaide: Pharmacy Department Royal Adelaide Hospital, 2011.
  70. Alam A, Gomes T, Zheng H, et al. Long-term analgesic use after low-risk surgery: A retrospective cohort study. Arch Intern Med 2012;172(5):425–30.
  71. Carroll I, Barelka P, Wang CK, et al. A pilot cohort study of the determinants of longitudinal opioid use after surgery. Anesth Analg 2012;115(3):694–702.
  72. Clarke H, Soneji N, Ko DT, Yun L, Wijeysundera DN. Rates and risk factors for prolonged opioid use after major surgery: population based cohort study. BMJ 2014;348:g1251.
  73. Hunter New England Local Health District. Reconsidering opioid therapy: NSW Government, 2014 opioid_therapy_May 2014.pdf [Accessed 12 July 2017].
  74. Larochelle MR, Liebschutz JM, Zhang F, Ross-Degnan D, Wharam JF. Opioid prescribing after nonfatal overdose and association with repeated overdose: A cohort study. Ann Intern Med 2016;164(1):1–9.
  75. Bazazi AR, Zaller ND, Fu JJ, Rich JD. Preventing opiate overdose deaths: Examining objections to takehome naloxone. J Health Care Poor Underserved 2010;21(4):1108–13.
  76. MacIntyre PE, Scott DA, Scott SA, Visser EJ, Walker SM, editors. Acute pain management: Scientific evidence. 3rd edn. Melbourne: Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine, 2010.
  77. Berna C, Kulich RJ, Rathmell JP. Tapering long-term opioid therapy in chronic noncancer pain: Evidence and recommendations for everyday practice. Mayo Clin Proc 2015;90(6):828–42.
  78. Corbett AD, Henderson G, McKnight AT, Paterson SJ. 75 years of opioid research: The exciting but vain quest for the Holy Grail. Br J Pharmacol 2006;147 Suppl 1:S153–62.
  79. Dahan A, Kest B, Waxman AR, Sarton E. Sex-specific responses to opiates: Animal and human studies. Anesth Analg 2008;107(1):83–95.
  80. Campesi I, Fois M, Franconi F. Sex and gender aspects in anesthetics and pain medication. Handb Exp Pharmacol 2012(214):265–78.
  81. Scott JC, Stanski DR. Decreased fentanyl and alfentanil dose requirements with age. A simultaneous pharmacokinetic and pharmacodynamic evaluation. J Pharmacol Exp Ther 1987;240(1):159–66.
  82. Minto CF, Schnider TW, Egan TD, et al. Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. Anesthesiology 1997;86(1):10–23.
  83. Macintyre P, Upton R. Acute pain management in the elderly patient. In: Macintyre P, Walker S, Rowbotham D, editors. Clinical pain management: Acute pain. 2nd edn. London: Hodder Arnold, 2008.
  84. Hurley RW, Adams MC. Sex, gender, and pain: An overview of a complex field. Anesth Analg 2008;107(1):309–17.
  85. Lee CW, Ho IK. Sex differences in opioid analgesia and addiction: Interactions among opioid receptors and estrogen receptors. Mol Pain 2013;9:45.
  86. Svetlik S, Hronova K, Bakhouche H, Matouskova O, Slanar O. Pharmacogenetics of chronic pain and its treatment. Mediators Inflamm 2013;2013:864319.
  87. Xu Y, Johnson A. Opioid therapy pharmacogenomics for noncancer pain: Efficacy, adverse events, and costs. Pain Res Treat 2013;2013. doi:10.1155/2103/864319.
  88. Somogyi AA, Barratt DT, Coller JK. Pharmacogenetics of opioids. Clin Pharmacol Ther 2007;81(3):429–44.
  89. Yang Z, Yang Z, Arheart KL, et al. CYP2D6 poor metabolizer genotype and smoking predict severe postoperative pain in female patients on arrival to the recovery room. Pain Med 2012;13(4):604–09.
  90. Kelly LE, Rieder M, van den Anker J, et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics 2012;129(5):e1343–47.
  91. Kirchheiner J, Schmidt H, Tzvetkov M, et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J 2007;7(4):257–65.
  92. Friedrichsdorf SJ, Nugent AP, Strobl AQ. Codeineassociated pediatric deaths despite using recommended dosing guidelines: Three case reports. J Opioid Manag 2013;9(2):151–55.
  93. Stamer UM, Stuber F, Muders T, Musshoff F. Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication. Anesth Analg 2008;107(3):926–69.
  94. Stamer UM, Stuber F. Genetic factors in pain and its treatment. Curr Opin Anaesthesiol 2007;20(5):478–84.
  95. Vuilleumier PH, Stamer UM, Landau R. Pharmacogenomic considerations in opioid analgesia. Pharmgenomics Pers Med 2012;5:73–87.
  96. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther 2014;95(4):376–82.
  97. Holmquist G. Opioid metabolism and effects of cytochrome P450. Pain Med 2009;10(S1):S20–29.
  98. Smith HS. Opioid metabolism. Mayo Clin Proc 2009;84(7):613–24.
  99. Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev 2009;41(2):89–295.
  100. Stamer UM, Stuber F. The pharmacogenetics of analgesia. Expert Opin Pharmacother 2007;8(14):2235–45.
  101. Manchikanti L, Ailinani H, Koyyalagunta D, et al. A systematic review of randomized trials of long-term opioid management for chronic non-cancer pain. Pain Physician 2011;14(2):91–121.
  102. Karlsson M, Berggren AC. Efficacy and safety of low-dose transdermal buprenorphine patches (5, 10, and 20 microg/h) versus prolonged-release tramadol tablets (75, 100, 150, and 200 mg) in patients with chronic osteoarthritis pain: A 12-week, randomized, open-label, controlled, parallel-group noninferiority study. Clin Ther 2009;31(3):503–13.
  103. Licina L, Hamsher C, Lautenschager K, et al. Buprenorphine/naloxone therapy for opioid refractory neuropathic pain following traumatic amputation: A case series. Mil Med 2013;178(7):e858–61.
  104. Simpson RW, Wlodarczyk JH. Transdermal buprenorphine relieves neuropathic pain: A randomized, double-blind, parallel-group, placebo-controlled trial in diabetic peripheral neuropathic pain. Diabetes Care 2016;39(9):1493–500.
  105. Guetti C, Angeletti C, Marinangeli F, et al. Transdermal buprenorphine for central neuropathic pain: Clinical reports. Pain Pract 2011;11(5):446–52.
  106. Wiffen PJ, Derry S, Moore RA, et al. Buprenorphine for neuropathic pain in adults. Cochrane Database Syst Rev 2015(9):CD011603.
  107. Pergolizzi J, Aloisi AM, Dahan A, et al. Current knowledge of buprenorphine and its unique pharmacological profile. Pain Pract 2010;10(5):428–50.
  108. Kress HG. Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine. Eur J Pain 2009;13(3):219–30.
  109. Dahan A, Yassen A, Romberg R, et al. Buprenorphine induces ceiling in respiratory depression but not in analgesia. Br J Anaesth 2006;96(5):627–32.
  110. Boom M, Niesters M, Sarton E, et al. Non-analgesic effects of opioids: Opioid-induced respiratory depression. Curr Pharm Des 2012;18(37):5994–6004.
  111. Hunter Integrated Pain Service. Health professional resources: Opioid selection. Newcastle, NSW: Hunter New England Health, 2013 au/__data/assets/pdf_file/0003/212961/Opioid_Selection. pdf [Accessed 12 July 2017].
  112. Lotsch J. Opioid metabolites. J Pain Symptom Manage 2005;29(5 Suppl):S10–24.
  113. Shaheed CA, Maher CG, McLachlan AJ. Investigating the efficacy and safety of over-the-counter codeine containing combination analgesics for pain and codeine based antitussives. Canberra: Therapeutic Goods Association, 2016 [Accessed 12 July 2017].
  114. Derry S, Moore RA, McQuay HJ. Single dose oral codeine, as a single agent, for acute postoperative pain in adults. Cochrane Database Syst Rev 2010(4):CD008099.
  115. Derry S, Karlin SM, Moore RA. Single dose oral ibuprofen plus codeine for acute postoperative pain in adults. Cochrane Database Syst Rev 2015;2:CD010107.
  116. Buckley NA, Faunce TA. Trials and tribulations in the removal of dextropropoxyphene from the Australian Register of Therapeutic Goods. Med J Aust 2013;199(4):257–60.
  117. Collins SL, Edwards JE, Moore RA, McQuay HJ. Single dose dextropropoxyphene, alone and with paracetamol (acetaminophen), for postoperative pain. Cochrane Database Syst Rev 2000(2):CD001440.
  118. Li Wan Po A, Zhang WY. Systematic overview of co-proxamol to assess analgesic effects of addition of dextropropoxyphene to paracetamol. BMJ 1997;315(7122):1565–71.
  119. Grape S, Schug SA, Lauer S, Schug BS. Formulations of fentanyl for the management of pain. Drugs 2010;70(1):57–72.
  120. Quigley C. Hydromorphone for acute and chronic pain. Cochrane Database Syst Rev 2002(1):CD003447.
  121. Felden L, Walter C, Harder S, et al. Comparative clinical effects of hydromorphone and morphine: A meta-analysis. Br J Anaesth 2011;107(3):319–28.
  122. Lugo RA, Satterfield KL, Kern SE. Pharmacokinetics of methadone. J Pain Palliat Care Pharmacother 2005;19(4):13–24.
  123. Weschules DJ, Bain KT, Richeimer S. Actual and potential drug interactions associated with methadone. Pain Med 2008;9(3):315–44.
  124. Fredheim OM, Moksnes K, Borchgrevink PC, Kaasa S, Dale O. Clinical pharmacology of methadone for pain. Acta Anaesthesiol Scand 2008;52(7):879–89.
  125. Weschules DJ, Bain KT. A systematic review of opioid conversion ratios used with methadone for the treatment of pain. Pain Med 2008;9(5):595–612.
  126. Klimas R, Mikus G. Morphine-6-glucuronide is responsible for the analgesic effect after morphine administration: A quantitative review of morphine, morphine-6-glucuronide, and morphine-3-glucuronide. Br J Anaesth 2014;113(6):935–44.
  127. Faura CC, Collins SL, Moore RA, McQuay HJ. Systematic review of factors affecting the ratios of morphine and its major metabolites. Pain 1998;74(1):43–53.
  128. Klepstad P, Dale O, Kaasa S, et al. Influences on serum concentrations of morphine, M6G and M3G during routine clinical drug monitoring: A prospective survey in 300 adult cancer patients. Acta Anaesthesiol Scand 2003;47(6):725–31.
  129. Vallejo R, de Leon-Casasola O, Benyamin R. Opioid therapy and immunosuppression: A review. Am J Ther 2004;11(5):354–65.
  130. Budd K. Pain management: Is opioid immunosuppression a clinical problem? Biomed Pharmacother 2006;60(7):310–17.
  131. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and metaanalysis. Lancet Neurol 2015;14(2):162–73.
  132. Lalovic B, Kharasch E, Hoffer C, et al. Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: Role of circulating active metabolites. Clin Pharmacol Ther 2006;79(5):461–79.
  133. Samer CF, Daali Y, Wagner M, et al. Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety. Br J Pharmacol 2010;160(4):919–30.
  134. Zwisler ST, Enggaard TP, Mikkelsen S, Brosen K, Sindrup SH. Impact of the CYP2D6 genotype on post-operative intravenous oxycodone analgesia. Acta Anaesthesiol Scand 2010;54(2):232–40.
  135. Kokki H, Kokki M, Sjovall S. Oxycodone for the treatment of postoperative pain. Expert Opin Pharmacother 2012;13(7):1045–58.
  136. Olkkola KT, Kontinen VK, Saari TI, Kalso EA. Does the pharmacology of oxycodone justify its increasing use as an analgesic? Trends Pharmacol Sci 2013;34(4):206–14.
  137. DePriest AZ, Miller K. Oxycodone/naloxone: Role in chronic pain management, opioid-induced constipation, and abuse deterrence. Pain Ther 2014;3(1):1–15.
  138. Nieminen TH, Hagelberg NM, Saari TI, et al. St John’s wort greatly reduces the concentrations of oral oxycodone. Eur J Pain 2010;14(8):854–59.
  139. Simopoulos TT, Smith HS, Peeters-Asdourian C, Stevens DS. Use of meperidine in patient-controlled analgesia and the development of a normeperidine toxic reaction. Arch Surg 2002;137(1):84–88.
  140. Silverman ME, Shih RD, Allegra J. Morphine induces less nausea than meperidine when administered parenterally. J Emerg Med 2004;27(3):241–43.
  141. Latta KS, Ginsberg B, Barkin RL. Meperidine: A critical review. Am J Ther 2002;9(1):53–68.
  142. Benner KW, Durham SH. Meperidine restriction in a pediatric hospital. J Pediatr Pharmacol Ther 2011;16(3):185–90.
  143. Tzschentke TM, Christoph T, Kogel BY. The mu opioid receptor agonist/noradrenaline reuptake inhibition (MORNRI) concept in analgesia: The case of tapentadol. CNS Drugs 2014;28(4):319–29.
  144. Vinik AI, Shapiro DY, Rauschkolb C, et al. A randomized withdrawal, placebo-controlled study evaluating the efficacy and tolerability of tapentadol extended release in patients with chronic painful diabetic peripheral neuropathy. Diabetes Care 2014;37(8):2302–09.
  145. Raffa RB, Buschmann H, Christoph T, et al. Mechanistic and functional differentiation of tapentadol and tramadol. Expert Opin Pharmacother 2012;13(10):1437–49.
  146. Riemsma R, Forbes C, Harker J, et al. Systematic review of tapentadol in chronic severe pain. Curr Med Res Opin 2011;27(10):1907–30.
  147. Biondi DM, Xiang J, Etropolski M, Moskovitz B. Evaluation of blood pressure and heart rate in patients with hypertension who received tapentadol extended release for chronic pain: A post hoc, pooled data analysis. Clin Drug Investig 2014;34(8):565–76.
  148. Xu XS, Smit JW, Lin R, et al. Population pharmacokinetics of tapentadol immediate release (IR) in healthy subjects and patients with moderate or severe pain. Clin Pharmacokinet 2010;49(10):671–82.
  149. Kemp W, Schlueter S, Smalley E. Death due to apparent intravenous injection of tapentadol. J Forensic Sci 2013;58(1):288–91.
  150. Dart RC, Cicero TJ, Surratt HL, et al. Assessment of the abuse of tapentadol immediate release: The first 24 months. J Opioid Manag 2012;8(6):395–402.
  151. Cepeda MS, Fife D, Ma Q, Ryan PB. Comparison of the risks of opioid abuse or dependence between tapentadol and oxycodone: Results from a cohort study. J Pain 2013;14(10):1227–41.
  152. Wiffen PJ, Derry S, Naessens K, Bell RF. Oral tapentadol for cancer pain. Cochrane Database Syst Rev 2015;9:CD011460.
  153. Afilalo M, Etropolski MS, Kuperwasser B, et al. Efficacy and safety of tapentadol extended release compared with oxycodone controlled release for the management of moderate to severe chronic pain related to osteoarthritis of the knee: A randomized, double-blind, placebo- and active-controlled phase III study. Clin Drug Investig 2010;30(8):489–505.
  154. Buynak R, Shapiro DY, Okamoto A, et al. Efficacy and safety of tapentadol extended release for the management of chronic low back pain: Results of a prospective, randomized, double-blind, placebo- and active-controlled Phase III study. Expert Opin Pharmacother 2010;11(11):1787–804.
  155. Lee YK, Ko JS, Rhim HY, et al. Acute postoperative pain relief with immediate-release tapentadol: Randomized, double-blind, placebo-controlled study conducted in South Korea. Curr Med Res Opin 2014;30(12):2561–70.
  156. Lange B, Kuperwasser B, Okamoto A, et al. Efficacy and safety of tapentadol prolonged release for chronic osteoarthritis pain and low back pain. Adv Ther 2010;27(6):381–99.
  157. Niesters M, Proto PL, Aarts L, et al. Tapentadol potentiates descending pain inhibition in chronic pain patients with diabetic polyneuropathy. Br J Anaesth 2014;113(1):148–56.
  158. Raffa RB, Friderichs E, Reimann W, et al. Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic. J Pharmacol Exp Ther 1992;260(1):275–85.
  159. Lee CR, McTavish D, Sorkin EM. Tramadol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs 1993;46(2):313–40.
  160. Stamer UM, Lehnen K, Hothker F, et al. Impact of CYP2D6 genotype on postoperative tramadol analgesia. Pain 2003;105(1–2):231–38.
  161. Radbruch L, Grond S, Lehmann KA. A risk–benefit assessment of tramadol in the management of pain. Drug Saf 1996;15(1):8–29.
  162. Lim A, Schug S. Tramadol versus morphine as oral stepdown analgesia after postoperative epidural analgesia. Reg Anesth Pain Med 2001;26(2):S133.
  163. Wilder-Smith CH, Hill L, Wilkins J, Denny L. Effects of morphine and tramadol on somatic and visceral sensory function and gastrointestinal motility after abdominal surgery. Anesthesiology 1999;91(3):639–47.
  164. Tarkkila P, Tuominen M, Lindgren L. Comparison of respiratory effects of tramadol and oxycodone. J Clin Anesth 1997;9(7):582–85.
  165. Tarkkila P, Tuominen M, Lindgren L. Comparison of respiratory effects of tramadol and pethidine. Eur J Anaesthesiol 1998;15(1):64–8.
  166. Jick H, Derby LE, Vasilakis C, Fife D. The risk of seizures associated with tramadol. Pharmacotherapy 1998;18(3):607–11.
  167. Gasse C, Derby L, Vasilakis-Scaramozza C, Jick H. Incidence of first-time idiopathic seizures in users of tramadol. Pharmacotherapy 2000;20(6):629–34.
  168. Nelson EM, Philbrick AM. Avoiding serotonin syndrome: The nature of the interaction between tramadol and selective serotonin reuptake inhibitors. Ann Pharmacother 2012;46(12):1712–16.
  169. Radbruch L, Glaeske G, Grond S, et al. Topical review on the abuse and misuse potential of tramadol and tilidine in Germany. Subst Abus 2013;34(3):313–20.
  170. Norrbrink C, Lundeberg T. Tramadol in neuropathic pain after spinal cord injury: A randomized, double-blind, placebocontrolled trial. Clin J Pain 2009;25(3):177–84.
  171. Australian medicines handbook 2015. Adelaide: Australian Medicines Handbook Pty Ltd, 2015. Available at http:// [Accessed 12 July 2017].
  172. McQuay HJ. Opioid clinical pharmacology and routes of administration. Br Med Bull 1991;47(3):703–17.
  173. Gammaitoni AR, Fine P, Alvarez N, McPherson ML, Bergmark S. Clinical application of opioid equianalgesic data. Clin J Pain 2003;19(5):286–97.
  174. Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part 2 – Guidance. Pain Physician 2012;15(3 Suppl):S67–116.
  175. American Academy of Pain Medicine, American Pain Society, American Society of Addiction Medicine. Public policy statement on the rights and responsibilities of health care professionals in the use of opioids for the treatment of pain: A consensus document from the American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine. Pain Med 2004;5(3):301–02.
  176. Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L. A comprehensive review of opioid-induced hyperalgesia. Pain Physician 2011;14(2):145–61.
  177. Low Y, Clarke CF, Huh BK. Opioid-induced hyperalgesia: A review of epidemiology, mechanisms and management. Singapore Med J 2012;53(5):357–60.
  178. Chang G, Chen L, Mao J. Opioid tolerance and hyperalgesia. Med Clin North Am 2007;91(2):199–211.
  179. Mao J. Opioid-induced hyperalgesia. Washington, DC: International Association for the Study of Pain, 2008 [Accessed 12 July 2017].
  180. Joo DT. Mechanisms of opioid tolerance: Merging evidence and therapeutic implications. Can J Anaesth 2007;54(12):969–76.
  181. Chu LF, Angst MS, Clark D. Opioid-induced hyperalgesia in humans: Molecular mechanisms and clinical considerations. Clin J Pain 2008;24(6):479–96.
  182. Reznikov I, Pud D, Eisenberg E. Oral opioid administration and hyperalgesia in patients with cancer or chronic nonmalignant pain. Br J Clin Pharmacol 2005;60(3):311–18.
  183. Ahmedzai SH, Boland J. Constipation in people prescribed opioids. BMJ Clin Evid 2006;12:2407.
  184. Rosow CE, Gomery P, Chen TY, et al. Reversal of opioidinduced bladder dysfunction by intravenous naloxone and methylnaltrexone. Clin Pharmacol Ther 2007;82(1):48–53.
  185. Kjellberg F, Tramer MR. Pharmacological control of opioidinduced pruritus: A quantitative systematic review of randomized trials. Eur J Anaesthesiol 2001;18(6):346–57.
  186. Mujtaba S, Romero J, Taub CC. Methadone, QTc prolongation and torsades de pointes: Current concepts, management and a hidden twist in the tale? J Cardiovasc Dis Res 2013;4(4):229–35.
  187. Fanoe S, Jensen GB, Sjogren P, Korsgaard MP, Grunnet M. Oxycodone is a
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