Drug Interactions in Pain Management

Steve Jones, Eric Visser, Stephan A Schug, Edward Shipton

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Abstract

Paracetamol + Warfarin

Paracetamol is widely considered the non-opioid of choice in anticoagulated patients. The use of paracetamol in this patient population has become controversial since a case-control study showed a 10 fold increased risk of an INR >6 associated with ingestion of more than 9.1 grams per week. Subsequent randomised controlled studies have yielded conflicting results. It is prudent to monitor INR particularly closely in regular users of warfarin and higher doses of paracetamol.

5-HT3 Antagonist Anti-Emetics + Analgesics

The best known interaction here is the one described between ondansetron and tramadol. Two RCTs showed increased tramadol consumption and reduced ondansetron efficacy with the use of the combination. Tramadol consumption was increased by 40-50% in both studies, while the efficacy of ondansetron as an anti-emetic seems to be affected, too. The authors conclude, that ondansetron should not be the first line anti-emetic when tramadol is used.

The observations are most likely best explained by a combined pharmacodynamic and a pharmacokinetic interaction between the two drugs. From a clinical point of view the combined use of tramadol and ondansetron should be avoided; we prefer low-dose droperidol anyway for cost reasons. It is possible, that other 5-HT3 antagonists do not necessarily share this problem; in particular granisetron and dolasetron are more selective 5-HT3 antagonists than ondansetron and granisetron is not metabolised by CYP450 2D6.

There is a less well-known interaction between 5-HT3 antagonists and paracetamol, which was first reported in 2006; a study in human volunteers showed complete inhibition of the analgesic effect of paracetamol by co-administration of granisetron or tropisetron. The results could not be confirmed with ondansetron; the authors of this study suggest that 5-HT1B and not 5-HT3 receptors are mediating thew analgesic effect of paracetamol.

Overall the clinical relevance of this one reported study are unclear; however, it might well be that use of granisetron and tropisetron, but possibly all 5-HT3 antagonists should be avoided with paracetamol.

Tramadol + TCAs/SSRIs

Tramadol inhibits noradrenaline and serotonin reuptake and also enhances serotonin release. A serotonergic syndrome may be precipitated by a variety of drugs including antidepressants, antiparkinsonian drugs, anti-migraine therapies and caution must be exercised when tramadol is used with these agents. These concerns are primarily based on theoretical considerations and limited case reports. It is important to watch for and recognise early signs of this syndrome. The same combination should be avoided in epileptics as both drugs lower the seizure threshold.

Tramadol + Morphine

The monoaminergic effects of tramadol act synergistically with the weak opioid effect of the M1 metabolite. How tramadol interacts with morphine is unclear, however an infra-additive effect is likely.

Low dose aspirin + NSAIDs

Aspirin has a pharmacodynamic (antiplatelet) effect lasting for days but a pharmacokinetic plasma half life of just 20 minutes. This disparity is due to covalent binding to platelet cyclo-oxygenase. Evidence suggests that if the binding sites are temporarily occupied by ibuprofen, the aspirin is denied access and will not work. The FDA recommends that aspirin be taken at least 8 hours after or 30 minutes before a dose of ibuprofen.

The combination of aspirin with non-selective NSAID increases the risk of gastropathy while the combination of aspirin with COX-2 inhibitors has been reported to deny any gastro-intestinal advantage this group may have. Pooled evidence does, however, suggest the combination with a COX-2 inhibitor has a lower gastro-intestinal risk.

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.

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