Potential for Drug-Drug Interactions with Adjunctive Tramadol Use in Treatment of Obsessive-Compulsive Disorder

In an outpatient psychiatry clinic, we recently diagnosed a 69-year-old man with obsessive-compulsive disorder (OCD) who had been prescribed the opioid analgesic tramadol for a chronic pain condition. Mindful that tramadol may interact with selective serotonin reuptake inhibitors (SSRIs), we consulted clinical practice guidelines to review OCD treatment options should switching away from tramadol be impractical.

In our review of the Canadian Psychiatric Association (CPA) clinical practice guidelines for anxiety disorders¹ and the more recent Anxiety Disorders Association of Canada (ADAC) guidelines,² we were reminded that tramadol itself is a proposed third-line treatment for OCD. In the CPA guidelines, consideration of tramadol as an adjunctive therapy is proposed.^{1(p47 S)} However, neither guideline mentions potential drug-drug interactions with other OCD treatments.

Tramadol is included in OCD treatment guidelines based on an uncontrolled open-label monotherapy trial in 7 treatment-resistant individuals³ and a single case study of tramadol in combination with fluoxetine.⁴ The evidence is graded as level 4 in both guidelines, reflecting its modest quality.

The potential for interactions between SSRIs and tramadol arises through both pharmacodynamic and pharmacokinetic factors.⁵ Beyond its actions on the opioid system, tramadol blocks serotonin reuptake and increases its basal release. It therefore increases serotonin availability, as do the recommended first-line treatments in OCD, the SSRIs, and other antidepressants considered second-line treatments in OCD, clomipramine and venlafaxine. Since tramadol is usually metabolized rapidly, problematic interactions based on pharmacodynamics alone are theoretically unlikely at standard doses in extensive metabolizers. However, the likelihood of toxicity is increased by pharmacokinetic factors. Tramadol is metabolized in the liver, with the enzyme CYP2D6 playing an important role.⁶ CYP2D6 is inhibited to varying degrees by SSRIs and other serotonergic antidepressants. Strong inhibitors (e.g., paroxetine and fluoxetine) or even a moderate inhibitor (e.g., sertraline) disrupt tramadol metabolism, which has to rely on an alternative pathway, meaning it may remain for longer and at greater concentrations in the blood and other organs. This could theoretically result in serotonin syndrome, a potentially lethal condition, and several cases due to interactions of tramadol with SSRIs have been reported.⁵ Finally, as the active metabolite of tramadol, produced exclusively by CYP2D6-mediated breakdown,⁶ accounts for the analgesic effect, in patients requiring pain relief, inhibition of CYP2D6 by an SSRI will compromise pain control.⁵

If tramadol is included in future clinical practice guidelines for OCD, potential interactions with other medications recommended as first-line treatments should be clearly described, especially as recent evidence suggests that clinician awareness of the potential for interactions between tramadol and SSRIs is low.⁷ While tramadol is suggested as an adjunctive therapy in the existing CPA guidelines, only a single case report is cited to support its combination with another recommended treatment. Conversely, a broader array of case reports⁵ suggests a risk of serotonin syndrome when tramadol is coprescribed with SSRIs, including paroxetine, fluoxetine, and sertraline—first-line treatments for OCD but inhibitors of CYP2D6. Clarification on how tramadol should be used as an adjunctive treatment is needed in future guidelines for the treatment of OCD.