Oxycodone: how did we get here and how do we fix it?

When oxycodone was first introduced into New Zealand in the early 2000s, it was regarded by many as a “new and improved” strong analgesic, with fewer adverse effects and perhaps none of the stigma associated with morphine. As a result, prescribing of oxycodone increased significantly over the next few years, reaching its peak in 2011/12. The number of prescriptions for morphine remained relatively stable over this same time period, suggesting that a new patient population being treated with oxycodone had been created.

Paralleling this surge in oxycodone use, reports of misuse and addiction emerged in New Zealand, following the trend observed in other countries with a longer history of oxycodone use. It has now become apparent that there is little or no advantage of oxycodone over morphine in terms of managing pain. Oxycodone is associated with the same adverse effects as morphine, and appears to be even more addictive than morphine. Therefore, there is no reason to continue to prescribe oxycodone instead of morphine (unless intolerable adverse effects have occurred with morphine), or to prescribe it when a less potent analgesic would be more appropriate.

The Wellington psychiatrist and addiction specialist Dr Jeremy McMinn commented in his interview in BPJ 61 (Jun, 2014), that in terms of the misuse of oxycodone in New Zealand, we are “looking at a disaster in the making”. Clinicians are urged to assess whether oxycodone is appropriate when initiating or continuing a prescription and, if necessary, make changes to their prescribing behaviour. How is it best to manage the problem with oxycodone? According to Dr McMinn: “Don’t get there in the first place”.

The international experience

Oxycodone was first synthesised in Germany in 1916 and became available for use in the United States in 1939. For many years it was used overseas as a component of combination short-acting analgesics, including paracetamol and NSAIDs. The controlled-release oxycodone-only formulation, OxyContin, was approved by the Food and Drug Administration (FDA) in the United States in 1996. In New Zealand, oxycodone was approved by Medsafe in 2001 and the oral forms (controlled and immediate-release) were subsidised on the New Zealand Pharmaceutical Schedule from 2005.

Since its release, the use of oxycodone has increased dramatically and many countries are now dealing with misuse and addiction issues. For example, in Ontario, Canada, the number of prescriptions for oxycodone increased by 850% between 1991 and 2007.¹ After controlled-release oxycodone was added to the Ontario state drug formulary there was a five-fold increase in oxycodone-related mortality, along with a 41% increase in overall opioid-related mortality.¹ Similar increases in the prescribing rates for oxycodone have also been observed in the USA. The national estimates for drug-related emergency department visits for oxycodone-containing medicines increased from 27.6 per 100 000 people in 2004 to 88.5 visits per 100 000 in 2009.² In Australia, the oxycodone supply increased 22-fold between 1997 and 2012, and oxycodone became the seventh most commonly prescribed medicine in general practice.³ By 2007, a national sample of injecting drug users found that 51% had reported using oxycodone.⁴

The situation in New Zealand

Between 2008 and 2013, the number of dispensed prescriptions for strong opioids in New Zealand has increased significantly (Figure 1). Much of this increase is attributed to a growing number of dispensed prescriptions for oxycodone. The most recent dispensing data from 2013 suggests that the number of prescriptions for oxycodone may be reaching a plateau, but the fact remains that oxycodone is a second-line option for moderate to severe pain, and should be dispensed considerably less than morphine.

The type of prescribers initiating oxycodone remained similar in 2013, compared with when first reported in 2011. Approximately 30% of prescriptions for oxycodone are written by General Practitioners and the remaining 70% are from other clinicians, e.g. those working in secondary care.⁵ In 2013, the proportion of prescriptions initiated in secondary care and continued in general practice was 17%, the same figure as in 2011 (Figure 2).⁵

Given the current best practice recommendations that oxycodone generally be reserved for second-line treatment after morphine, it is concerning that approximately 80% of patients prescribed oxycodone for the first time in 2013 did not have a previous prescription for morphine in the preceding 12 months.⁵ This suggests that the majority of first-time prescribing of oxycodone is occurring before a trial of morphine, or alternatively, patients are being treated in hospital with parenteral morphine or pethidine and discharged with oral oxycodone.

For further information see: "Oxycodone use still increasing", BPJ 36 (Jun, 2011). "Update on Oxycodone what can primary care do about the problem", BPJ 44 (May 2012).

The strong marketing of oxycodone (See: “The oxycodone marketing campaign), along with its rapid rise in popularity, means that many aspects of its pharmacology and general use may be misunderstood. There are few head-to-head trials comparing oxycodone with morphine or other opioids, yet several claims have been made about its alleged superiority, many of which are not entirely accurate. There is no debating that oxycodone is an effective analgesic, however, there is no compelling clinical reason to choose it over morphine, and the associated risks and problems with its use, clearly place oxycodone as a second-line option.

Potency: oxycodone is a strong opioid

Despite its name, oxycodone is not a “natural version of codeine” or a “gentle analgesic” – it is approximately twice as potent as morphine, i.e. 10 mg of oxycodone is equivalent to 15–20 mg of morphine.^{6, 7} A clinical trial reported that oral controlled-release oxycodone was twice as potent as oral controlled-release morphine in patients who received single doses for post-operative pain following hysterectomy.⁸ For total and peak analgesic effects, the doses of 20 mg and 40 mg oxycodone were comparable to morphine doses of 45 mg and 90 mg, respectively.⁸

Oxycodone is approximately 7.5 – 20 times more potent than codeine, i.e. 10 mg of oxycodone is equivalent to 75-200 mg of codeine.⁶

The stigma associated with morphine is a reason that some patients are reluctant to use it, however, the same patients are comfortable using oxycodone. When discussing appropriate analgesic treatments with patients, clinicians need to ensure that patients understand that oxycodone is used for the same purpose as morphine and is actually more potent.

Addictive potential: oxycodone rates higher than morphine

All opioid analgesics (including weak opioids) are potentially addictive, but the marketing campaign for oxycodone promoted the belief that it had a lower addictive potential than other strong opioids. However, the literature suggests that oxycodone actually has a higher addictive potential than morphine.

A systematic review of nine randomised trials compared the likeability and likelihood of misuse of oral oxycodone, morphine and other selected opioids in recreational drug users and people with a history of opioid misuse. It was found that oxycodone was more favoured and more likely to be misused than either morphine or hydrocodone (not available in New Zealand).⁹ Oxycodone demonstrated high subjective attractiveness ratings with a few negative ratings across the majority of studies included in the review. Oxycodone was also associated with consistently higher “take again” ratings than morphine.⁹

The addictive potential of strong opioids needs to be discussed with and understood by patients before they are prescribed. A psychological assessment of the likelihood of addiction forms part of the risk-benefit analysis for the decision to prescribe an opioid.

Renal impairment: use oxycodone with caution

Many clinicians have prescribed oxycodone in preference to morphine due to the belief that oxycodone is safer in patients with renal impairment. However, oxycodone should be used with caution in patients with renal failure and prolonged use avoided in patients with an eGFR < 10 mL/min/1.73 m² (due to the risk of accumulation of metabolites).¹⁰ Case reports of oxycodone toxicity in patients with renal impairment have been reported, along with increased sedation.¹¹

In many cases, morphine can still be safely used in patients with renal impairment, if it is dosed carefully; use the lowest effective dose and consider the cumulative effect. Patients will have an individual response to morphine in terms of its effect on their renal function.

Fentanyl is regarded as the safest strong opioid for patients with renal impairment (although does have other adverse effects).¹⁰ Methadone is also an appropriate option for patients with renal impairment, but can be complex to dose and should only be prescribed if the clinician is familiar with its use.¹⁰ Codeine, pethidine and tramadol should be avoided in people with renal impairment.

The two main metabolites of oxycodone are oxymorphone (a very potent analgesic) and noroxycodone (a weak analgesic), which are both renally excreted.⁶ It is reported that up to 19% of oxycodone is eliminated unchanged in the urine.¹² There is limited data on renal clearance of oxycodone. A small study in people with mild-to-moderate renal dysfunction showed that the peak plasma oxycodone and noroxycodone concentrations were approximately 50% and 20% higher, respectively, than in people without renal failure.¹³ The AUC (area under the curve – a measure of total exposure to a drug) values for oxycodone, noroxycodone and oxymorphone were approximately 60%, 50% and 40% higher in people with renal dysfunction than in people with normal renal function, respectively.¹³

For further information see: “Fentanyl patches to be available without Special Authority in 2011”, BPJ 33 (Dec, 2010). “Methadone – safe and effective use for chronic pain” BPJ 18 (Dec, 2008).

Adverse effect profile: similar overall to morphine

Overall, oxycodone and morphine have similar adverse event profiles that are consistent with other opioid analgesics. The most common adverse events reported with use of oxycodone (with approximate rates) are constipation (25–30%), nausea (25%), drowsiness (15%), vomiting (10–15%) and pruritis (10–15%).⁶ It has been reported that constipation occurs more frequently in people taking oxycodone compared to those taking morphine.⁶ The incidence of the other adverse effects are generally similar, however, a few studies have reported that the rates of nausea and vomiting, hallucinations and pruritis may be lower in people taking oxycodone compared to those taking morphine.⁶

Oxycodone, unlike morphine, is mainly metabolised by the CYP3A and CYP2D6 enzymes in the liver.⁷ The involvement of CYP3A in the metabolism of oxycodone makes it more prone to interactions with drugs that inhibit or induce this enzyme. ⁷ Inhibitors of CYP3A, e.g. ritonavir, clarithromycin, itraconazole, miconazole and grapefruit juice potentiate the effect of oxycodone, resulting in an increased risk of adverse effects.⁷ Inducers of CYP3A, e.g. St John’s wort and rifampicin, reduce exposure to oxycodone.⁷ This may result in people taking higher doses of oxycodone, which becomes problematic if the enzyme-inducing medicine is stopped.

CYP2D6 is a highly polymorphic enzyme; gene mutations and deletions cause the enzyme to be non-functional or over-expressed. This results in people having phenotypes for poor, intermediate, extensive or ultra-rapid metabolisers of drugs which are dependent on this enzyme. Most evidence has found that the CYP2D6 genotype does not have a significant influence on the analgesic effect of oxycodone or risk of adverse effects, but this is an ongoing area of research.⁷