Which analgesics, in addition to paracetamol, could be given to a patient with spinal stenosis, who

Fråga: Which analgesics, in addition to paracetamol, could be given to a patient with spinal stenosis, who is also treated with tranylcypromine for depression, and who does not tolerate non-steroidal anti-inflammatory drugs (NSAIDs)? Her present drug treatment also includes spironolactone, bendroflumethiazide, insulin, levothyroxine, rivastigmin, propiomazine and zolpidem.

Sammanfattning: Due to their lack of serotonergic effects and the absence of any reported severe interaction cases, morphine, codeine and buprenorphine have been suggested to be relatively safe in combination with monoamine oxidase inhibitors.

Svar: Tranylcypromine is an irreversible, unselective monoamineoxidase inhibitor (MAOi), acting by increasing the levels of norepinephrine, epinephrine, dopamine and serotonin in the central nervous system and other body tissues. Concomitant intake of tyramine-rich food (e.g. ripe cheese, pickled herring), or any indirectly acting sympatomimetic or serotonergically active drug may cause severe side-effects, including hypertensive crisis and serotonergic syndrome, and is thus strictly contraindicated (1).

There has also been a general warning concerning the use of opioid analgesics together with tranylcypromine. This warning is based partly on the risk for additive sedation from MAOi´s and central nervous system depressants, but primarily on several severe or fatal cases resulting from the combination of MAOi´s and pethidine. However, it has been suggested that these severe reactions are serotonergic crises, and related to the serotonin reuptake inhibitory properties of pethidine. Accordingly, opioid analgesics can be divided into two groups, with (pethidine, tramadol, dextrometorphan and methadone) or without serotonergic effects (morphine, codeine, buprenorphine and oxycodone). For a third group, including fentanyl, propoxyphene and pentazocine, the serotonergic profile has not been well characterised. For the opioids without serotonergic activity, there are no reported severe interaction (hypertension, rigidity etc) cases with MAOi´s (2). Uneventful use of morphine in patients treated with tranylcypromine has been reported in at least 14 patients, but there are also a few reports of reversible hypotension or prolonged opioid effect in concomitant use (3).

In addition to the MAO enzyme, tranylcypromine inhibits the liver enzyme CYP2A6, which metabolises e.g. nicotine to cotinine (4). CYP2A6 is not, however, responsible for the metabolism of any analgesic drug, and the risk of pharmacokinetic interactions is thus small.

In the present case, we suggest the use of codeine (which is metabolised into active morphine) or morphine in carefully titrated doses. If the reason for intolerance to NSAIDs is gastric uncomfort, an alternative would be to give a combination of an NSAID and a proton pump inhibitor. However, it should be noted that NSAIDs may counteract the effect of diuretics and also cause renal damage in susceptible patients. Dollery C Sir, editor. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone; 1999 Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth 2005;95(4):434-441 Baxter K (Ed), Stockley´s Drug interactions. London: Pharmaceutical Press. Electronic version (cited 2008-04-29) Zhang W, Kilicarslan T, Tyndale RF, Sellers EM. Evaluation of methoxsalen, tranylcypromine, and tryptamine as specific and selective CYP2A6 inhibitors in vitro. Drug Metab Dispos 2001;29(6):897-902.