Buprenorphine interactions

Although there is significant confusion in the literature, buprenorphine is most commonly classified as a (partial) mu agonist/kappa antagonist. There is consensus that in the relatively ‘low doses’ used in clinical pain management, (5-100 mcg per hour), buprenorphine behaves like a ‚full‘ mu agonist. The partial agonist/antagonist effects seem only to become relevant for analgesia in very high doses used to treat opioid addiction (8-32 mg per day).

In patients on ‘analgesic doses’ of buprenorphine (eg transdermal), one can continue to use opioid analgesics for breakthrough pain in the usual way with good effect. The partial agonist/antagonist effect on supplemental opioid analgesia is not a major clinical issue. Other alternatives include sublingual buprenorphine or tramadol.

When treating acute pain after major surgery or trauma in patients on ‘high dose’ sublingual buprenorphine for addiction, continue the buprenorphine, using maximal multimodal analgesia including ketamine and neural blockade, supplemented with opioid PCA (using higher bolus doses) and monitoring the patient closely for adverse effects. In our experience, many patients undergoing major emergency surgery seem to do well with continuation of high dose sublingual buprenorphine and PCA fentanyl or morphine in appropriate doses. Conversion to standard opioids is complicated and often unnescessary.

Methadone interactions

Because methadone ‘saturates’ CYP450 (3A4) at low plasma levels (low hepatic clearance) compared with other opioids, it’s very ’susceptible‘ to;

  • The effects of a 30-fold variation in CYP450 enzyme activity between patients (fast, medium or slow methadone metabolisers), thus explaining the wide range of t1/2 (5-150 hours) and in part, highly variable clinical responses to methadone loading.
  • ‘Plasma accumulation‘, as the dose or frequency increases (the ’saturated‘ CYP450 can’t ‚burn off‘ the excess methadone):
  • Complex interactions with many drugs that share CYP450 for metabolism, particularly anticonvulsants, antidepressants, anti-microbial and antiretrovirals.

When prescribing methadone, always think about drug interactions at CYP450. Interactions are complex, with either induction (eg. phenytoin, rifamycins) or suppression (eg. fluvoxamine, fluoroquinalones, macrolides) of enzyme activity affecting methadone clearance, sometimes resulting in either withdrawal or accumulation respectively.

Methadone is highly-bound to plasma acute phase reactants (a1-acid glycoprotein), with the free methadone concentration decreasing when the level of phase reactants is raised (the free methadone is ‘mopped up’) such as in cancer or sepsis, leading to reduced analgesia or in rare cases withdrawal.

There are also substantial risks of over-sedation when methadone is combined with benzodiazepines, alcohol or THC.

Methadone, prolongs the QT interval in a dose dependent fashion (usually in doses greater than 200 mg per day) with case reports of Torsades de Pointes and VT. Check an ECG before commencing methadone, keep doses low and consider potential interaction with other drugs and conditions that prolong the QT interval.