Oxycodone × Pregabalin

Pregabalin and oxycodone depress the central nervous system (CNS) through different pathways, and their effects add up. Oxycodone, like all opioids, blunts the respiratory centre. Pregabalin on its own causes somnolence, dizziness and, rarely, severe respiratory depression, and the risk rises with other CNS depressants (pregabalin SmPC, EMA, section 4.4). There is no pharmacokinetic interaction. Pregabalin is barely metabolised and leaves the body unchanged in urine, and in a study with oxycodone the levels of both drugs stayed the same (pregabalin SmPC, EMA, section 4.5; FDA label of pregabalin, section 7). Pregabalin does, however, add to the cognitive and motor impairment that oxycodone causes (pregabalin SmPC, EMA, section 4.5). Both drugs slow the gut: constipation, paralytic ileus and intestinal obstruction have been reported with the combination (pregabalin SmPC, EMA, section 4.4).

Somnolence, slowed thinking, dizziness, poor coordination and falls, especially in older patients. In severe cases, slow shallow breathing, deep sedation, coma and death: such cases were reported after marketing in patients taking pregabalin with opioids and other CNS depressants (pregabalin SmPC, EMA, section 4.5; oxycodone SmPC, AEMPS, section 4.5). In an observational study, patients taking pregabalin with an opioid had a 1.68-fold higher risk of opioid-related death than those on an opioid alone. The rise was already present at pregabalin doses of 300 mg per day or less (pregabalin SmPC, EMA, section 4.4). The risk is highest at the start of treatment and after a dose increase, and in patients with impaired breathing, renal failure or older age (pregabalin SmPC, EMA, section 4.4; FDA label of oxycodone, section 5.2). Constipation up to intestinal obstruction is a separate concern.

The combination is allowed, but under strict limits. The oxycodone SmPC names pregabalin among CNS depressants. It requires limiting the dose and duration of concomitant use and reserving such pairs for patients with no alternative treatment options (oxycodone SmPC, AEMPS, sections 4.4 and 4.5; FDA label of oxycodone, sections 5.3 and 7). Use the lowest effective dose and the shortest possible course (oxycodone SmPC, AEMPS, section 4.4). When starting oxycodone in a patient already on pregabalin, begin with one-third to one-half of the usual starting dose of oxycodone and consider a lower pregabalin dose (FDA label of oxycodone, section 2.6). When adding pregabalin to an opioid, start it at a low dose (FDA label of pregabalin, section 5.5) and adjust it to renal function, because renal impairment, lung disease and older age raise the risk of respiratory depression (pregabalin SmPC, EMA, sections 4.2 and 4.4). Warn the patient and carers about the signs of respiratory depression and sedation and watch for them, especially in the first days and after every dose increase (oxycodone SmPC, AEMPS, section 4.4; pregabalin SmPC, EMA, section 4.4). The FDA advises considering an opioid overdose reversal agent, naloxone or nalmefene, for this combination (FDA label of oxycodone, section 5.3). If respiratory depression appears, reduce or withdraw the CNS depressants, including pregabalin (FDA label of pregabalin, section 5.5). Consider measures against constipation, especially in women and older patients (pregabalin SmPC, EMA, section 4.4).