Introduction

Tramadol is an oral, synthetic, centrally active opioid-like analgesic for the treatment of moderate to severe pain. Although not completely understood, its mechanism of action includes agonist activity at the m-opioid receptors, as well as reuptake inhibition of the neurotransmitters serotonin and nor-epinephrine.¹

Tramadol is available as a single ingredient extended-release tablet (Ralivia, Tridural, Zytram XL) and as an immediate-release formulation in a combination product with acetaminophen (Tramacet).^2–5 Its efficacy and safety have been established in many randomized controlled trials. In the treatment of postoperative pain, tramadol has equivalent analgesia to codeine and hydrocodone, with reduced adverse effects, such as constipation, nausea and vomiting.^6–8 Tramadol is also thought to possess a lower abuse potential than other opioid analgesics, making it a popular choice for the treatment of chronic pain, particularly in patients with a history of or current substance abuse.^9,10

Inpatients often have multiple comorbidities for which a variety of medications are prescribed. Used for mood elevation and control of chronic pain, antidepressants are one of the most common classes seen.¹⁰ Health care professionals must be aware of the potential drug interactions when tramadol is combined with antidepressants.¹¹ To document such interactions, a literature search was conducted in the following databases: Medline via Ovid, Asksam (including a search in the Canadian Adverse Reaction Newsletter by Health Canada) and Reactions via WebSpirs (1983–2008). The Canadian manufacturer of Tramacet was also contacted for additional case reports of serotonin syndrome related to tramadol interactions. Evidence collected confirmed that the combination of tramadol with antidepressants may put the patient at risk of experiencing seizures, serotonin syndrome or decreased analgesic effects.

Seizures

Tramadol has been associated with seizures, typically when taken at higher than recommended dosages, although in some cases, usual doses were involved.^2–5 This dose-dependent mechanism is believed to result from the ability of tramadol to lower the seizure threshold. Furthermore, concomitant use of tramadol with other agents known to lower the seizure threshold (e.g., selective serotonin reuptake inhibitors [SSRIs], tricyclic antide-pressants [TCAs], monoamine oxidase inhibitors [MAOIs] and bupropion) further increases this risk.¹² Patient-specific factors may also play a role (e.g., history of seizures or seizure disorder, head trauma, metabolic disturbances, abuse or withdrawal of alcohol/drugs, CNS infections).^2–5

Serotonin syndrome

The serotonin syndrome is a rare, but potentially fatal complication that most commonly occurs with the coadministration of 2 or more drugs that affect the serotonin system.¹⁰ It usually presents as a triad of altered mental status (e.g., agitation, confusion, delirium, hallucinations, hyperactivity, hypomania), autonomic hyperactivity (e.g., diarrhea, flushing, diaphoresis, fever, mydriasis, hyper/hypotension) and neuromuscular abnormalities (e.g., hyperreflexia, increased muscle tone, restlessness, rigidity, tremor, shivering).¹³ Although most often feared when patients are prescribed multiple antidepressants, the serotonin syndrome is also associated with tramadol when used concomitantly with a single antidepressant. Increased concentrations of serotonin through reuptake inhibition can lead to peripheral and central 5-HT receptor overstimulation, which is thought to be responsible for inducing this syndrome.¹⁰ The risk for developing serotonin syndrome and seizures has resulted in the absolute contraindication of MAOIs when used concurrently or within 14 days of tramadol initiation.^2–5

Several documented cases of serotonin syndrome have been attributed to the coadministration of tramadol with SSRIs, TCAs, venlafaxine, and mirtazapine (Table 1).^10,14–24 In the majority of reports, the serotonin syndrome typically developed within hours to a few days following the administration of a new serotonergic agent or a dosage increase in either tramadol or the antidepressant. Doses of both tramadol and the antidepressant varied from within the normal range to above those recommended. From these cases, we can deduce that although serotonin syndrome is thought to be a dose-independent phenomenon, a critical level of serotonin is required to develop this reaction.¹⁰ Following discontinuation or dose reduction of tramadol and the concomitant antidepressant, gradual resolution of symptoms and complete recovery were seen in all cases except one. In the one fatal case, deterioration occurred over 4 days and was complicated by cardiovascular manifestations.²⁴ Despite these reported cases, serotonin syndrome is an extremely rare event, with clinical trials and postmarketing experience reporting an incidence of less than 1% [Shiri Iskander, Janssen-Ortho, personal communication, September 18, 2008]. Nevertheless, health care professionals should be vigilant when tramadol and an antidepressant are prescribed concomitantly, bearing in mind that combined use is not necessarily contraindicated in all situations.

TABLE 1. Case reports of serotonin syndrome induced by concomitant use of tramadol with antidepressants14–24

Decreased analgesic effect

Tramadol is metabolized by the isoenzyme CYP2D6 to its active metabolite, O-desmethyltramadol (M1). As with tramadol, M1 binds to the m-opioid receptor to exert its analgesic effect; however, its binding affinity is 200 times more potent than that of the parent compound.^2–5 Animal studies have also shown M1 as being up to 6 times more potent in producing analgesia.^2–5 Drugs known to inhibit CYP2D6, such as amitriptyline, fluoxetine and paroxetine may result in higher serum concentrations of the parent drug and lower serum concentrations of its active metabolite. Theoretically, this interaction may result in reduced analgesic effect of tramadol.¹² However, as unresolved pain is often masked by additional analgesic use, it becomes difficult to document this interaction clinically.

Clinical management

Health care professionals need to be aware of the interaction between tramadol and antidepressants.¹⁰ Understanding the pharmacological mechanism responsible for the 3 potential interactions aids in the clinical management and monitoring of the patient. When tramadol is used concomitantly with antidepressants, such as SSRIs, TCAs, venlafaxine, mirtazapine and bupropion, close observation of the patient for signs and symptoms of seizures, serotonin syndrome and possibly reduced analgesic efficacy should be implemented.²⁵ In situations where additional risk factors exist, the avoidance of tramadol and the use of an alternative analgesic with similar potency (e.g., codeine) may be a safer alternative, since no antidepressant combined with tramadol can be considered safer than another at this time.^6,8,26

Acknowledgments

The author would like to thank Anne Massicotte, BPharm, MSc, of the Civic Campus of the Ottawa Hospital for her revisions to this article.