#F012 Increased use of oxycodone in pain management

version française

What is the subject ?

The alarming increase in the use of oxycodone in pain management.

Why are we addressing this subject ?

Oxycodone was the first drug to be at the centre of the opioid crisis in the United States. The vast majority of patients reporting a use disorder initially took oxycodone as part of a medical prescription.
In France, its involvement in toxic deaths caused by painkillers quadrupled between 2013 and 2017. In 2017, although morphine was still the leading third step opioid analgesic used in France, it was closely followed by oxycodone, with a sharp increase of consumption of the latter (+738% since 2006) in both outpatient and hospital settings.
Like morphine, oxycodone is a strong opioid receptor agonist. In recent years, prescriptions of oxycodone in France have risen at a worrying rate, despite the fact that it offers no pharmacological advantage over morphine. In the absence of guidelines regarding first choice opioid treatments, we wish to point out that the pharmacokinetic and pharmacodynamic differences between oxycodone and morphine suggest that oxycodone poses a greater risk than morphine.
Oxycodone has a greater and longer-lasting dopaminergic action than morphine, which could be associated with a higher addictive profile. Compared to morphine, oxycodone is also likely to expose patients to more risks related to drug interactions, in particular heart rhythm disorders. Finally, it has no advantage in terms of frequent adverse effects, particularly the risk of constipation, which is strictly comparable to that of morphine.

The opinion of the SFPT (French Society of Pharmacology and Therapeutics)

Whether in terms of efficacy, adverse reactions, pharmacokinetic and pharmacodynamic characteristics or risk of misuse, there is no scientific basis for preferring an initial prescription of oxycodone to morphine. Morphine remains the preferred opioid for analgesia.
Reminder: Opioids are not indicated for neuropathic pain

For more information

No pharmacokinetic or pharmacodynamic advantage

Contrary to frequent belief, oxycodone's analgesic action is not twice as powerful as that of morphine. Intravenously, these two molecules are equivalent in terms of analgesia. The different analgesia ratio (1.5-2 morphine equivalents) per oral route is only related to the greater oral bioavailability of oxycodone compared with morphine (30%) (1). However, the oral bioavailability of oxycodone is variable (between 60% and 80%), which may lead to variability in clinical response, particularly in the elderly, where drug bioavailability is increased. Oxycodone binds more to plasma proteins (45%) than morphine (30%), which may lead to a risk of overdose in the elderly et/or malnourished patients.

While morphine is glucoronoconjugated and undergoes an enterohepatic cycle, oxycodone is metabolised by cytochromes P450 (mainly CYP3A4/5, and a minor route by CYP2D6) and therefore carries a risk of drug interaction. Its use is not recommended with inhibitors (e.g. azole antifungals) and enzyme inducers (e.g. rifampicin).

Oxycodone may increase the QT interval of the electrocardiogram in a dose-dependent manner (3,4). Unlike morphine, oxycodone tends to be lipophilic, which may prolong its elimination half-life in the elderly due to the increase in the fat compartment with age (5,6,7).

Safety profile

 Increased risk of drug use disorders?

With regard to its action on the dopaminergic system, several studies have demonstrated a greater and longer-lasting dopaminergic action than with morphine (7,8,9). Its greater lipophilicity may also contribute to this risk. A study comparing the persistence of oxycodone prescription versus tapentadol in the postoperative period concluded that oxycodone was more persistent. Therefore, there are several arguments suggesting that oxycodone presents a high risk of use disorders (10).

Oxycodone was the first drug at the centre of the opioid crisis in the United States. According to current addictovigilance data in France, the vast majority of reports of drug use disorders involving oxycodone concern subjects initially exposed to this drug as part of an analgesic treatment (73%).

 Poisoning

The involvement of oxycodone in toxic analgesic deaths in France quadrupled between 2013 and 2017, particularly in potentially avoidable accidental contexts due to unfamiliarity with the product (self-medication as sleep pills), or in a festive context. In Australia, recent findings on opioids involved in emergency admissions showed that oxycodone was the second most common substance involved in ED admissions over the last ten years, after codeine. However, the number of admissions involving oxycodone has continued to rise, approaching that of codeine (11).

Frequent adverse reactions

Oxycodone and morphine present similar adverse effects, attributable to the opioid class, and are generally dose-dependent. Respiratory distress is classically observed in cases of overdose, and constipation is very common. To date, there are no studies showing a difference in the frequency of constipation between morphine and oxycodone. Two meta-analyses of clinical trials recommended morphine as the opioid analgesic of choice, particularly in view of its lower cost. The first meta-analysis, comparing oxycodone with morphine alone, concluded that the efficacy and safety profile were comparable, with an OR=1.04 (IC95% 0.77-1.1) for constipation (12). The same results were found in the second meta-analysis with an OR=0.98 (IC95% 0.82-1.16 (13).

Overlapping contraindications and precautions for use

The precautions for use of oxycodone and morphine are similar in case of renal or hepatic failure, i.e. adjustment of dosage and clinical and biological monitoring. The only additional contraindication to morphine compared with oxycodone concerns cases of severe hepatic insufficiency with encephalopathy.

References

1. Table pratique d'équiantalgie des opoïdes forts https://sfap.org/system/files/table_pratique_dequiantalgie_octobre_2016.pdf (in French)
2. Gaskell H, Derry S, Stannard C, Moore RA. Oxycodone for neuropathic pain in adults. Cochrane Database Syst Rev. 2016;7(7).
3. Behzadi M, Joukar S, Beik A. Opioids and Cardiac Arrhythmia: A Literature Review. Med Princ Pract 2018;27:401-414.
4. Fanoe S, Jensen GB, Sjøgren P, Korsgaard MP, Grunnet M. Oxycodone is associated with dose-dependent QTc prolongation in patients and low-affinity inhibiting of hERG activity in vitro. Br J Clin Pharmacol. 2009;67:172-9.
5. Kinnunen M, Piirainen P, Kokki H, Lammi P, Kokki M. Updated Clinical Pharmacokinetics and Pharmacodynamics of Oxycodone. Clin Pharmacokinet. 2019;58:705-725.
6. Tan HP, Conroy T. The Effectiveness of Intravenous Oxycodone in the Treatment of Acute Postoperative Pain: A Systematic Review. J Perianesthesia Nurs Off J Am Soc PeriAnesthesia Nurses 2018;33:865-879.
7. Capriz F, Chapiro S, David L, et al. Consensus multidisciplinaire d’experts en douleur et gériatrie : utilisation des antalgiques dans la prise en charge de la douleur de la personne âgée (hors anesthésie). Douleurs Éval - Diagn – Trait 2017;18:234‑
8. Remillard D, Kaye AD, McAnally H. Oxycodone’s Unparalleled Addictive Potential: Is it Time for a Moratorium? Curr Pain Headache Rep. 2019;23:15.
9. Vander Weele CM, Porter-Stransky KA, Mabrouk OS, Lovic V, Singer BF, Kennedy RT, Aragona BJ. Rapid dopamine transmission within the nucleus accumbens: dramatic difference between morphine and oxycodone delivery. Eur J Neurosci 2014;40:3041-3054.
10. Lam T, Xia T, Biggs N, Treloar M, et al. Effect of discharge opioid on persistent postoperative opioid use: a retrospective cohort study comparing tapentadol with oxycodone. Anaesthesia 2023;78:420-431.
11. Lam T, Hayman J, Berecki-Gisolf J, et al. Pharmaceutical opioid poisonings in Victoria, Australia: Rates and characteristics of a decade of emergency department presentations among nine pharmaceutical opioids. Addiction 2022;117:623-636.
12. Guo KK, Deng CQ, Lu GJ, Zhao GL. Comparison of analgesic effect of oxycodone and morphine on patients with moderate and advanced cancer pain: a meta-analysis. BMC Anesthesiol 2018;18:132.
13. Schmidt-Hansen M, Bennett MI, Arnold S, Bromham N, Hilgart JS. Efficacy, tolerability and acceptability of oxycodone for cancer-related pain in adults: an updated Cochrane systematic review. BMJ Support Palliat Care 2018;8:117-118.