Concomitant Use of Antidepressants, Anticonvulsants Increase Ziconotide Side Effects

By Frances Morin

NATIONAL HARBOR, Md -- March 24, 2015 -- The common use of antidepressants and anticonvulsants among patients treated with intrathecal ziconotide for chronic pain is associated with increased side effects of cognitive impairment and alertness, according to a study presented here on March 21 at the 31st Annual Meeting of the American Academy of Pain Medicine (AAPM).

“Due to potential additive effects on alertness and cognition, dosage adjustments may be required when intrathecal ziconotide is used in conjunction with other central nervous system depressant medications,” wrote Mark Wallace, MD, University of California at San Diego, San Diego, California, and colleagues in their presentation.

Ziconotide is often used in the management of severe chronic pain in patients who fail to respond to other treatment and require intrathecal therapy, involving an implantable drug infusion system.

Three randomised clinical trials for ziconotide have shown that patients receiving the therapy also typically received ≥1 concomitant non-intrathecal medications, the most common being antidepressants (66%), anxiolytics (52%), anticonvulsants (47%), neuroleptics (46%), and sedatives (34%).

With the drug classes sharing common side effects, Dr. Wallace and colleagues sought to evaluate whether the effects are exacerbated when the drugs are combined. The analysis included 220 patients with severe chronic pain participating in an open-label extension study assessing the long-term effects of the drug. Patients were in the study for a mean duration of 198 days.

Among the participants, 94 (42.7%) received concomitant antidepressants and anticonvulsants; 57 (25.9%) received antidepressants but not anticonvulsants; 32 (14.5%) received anticonvulsants but not antidepressants; and 37 (16.8%) received neither antidepressants nor anticonvulsants during the study period.

Antidepressants commonly used included venlafaxine, amitriptyline, sertraline, trazodone, and bupropion, while anticonvulsants, included gabapentin, clonazepam, tiagabine, topiramate, and valproic acid.

Patients with concomitant use of antidepressants only had the highest mean daily dose of ziconotide (10.8 μg per day).

With nearly all (99.1%) patients experiencing ≥1 adverse events (AEs) during the long-term study, the AE that stood out as having the strongest association with the drug combinations was somnolence, which occurred in 42.6% of patients receiving antidepressants and anticonvulsants in addition to ziconotide, compared with 18.9% of those who only received ziconotide.

Patients on antidepressants and anticonvulsants along with ziconotide also had more than 10% higher incidence of other AEs, compared with those who received neither, including
depression (23.4% vs 8.1%), aphasia (22.3% vs 8.1%), sweating (20.2% vs 8.1%), hypertonia (19.1% vs 8.1%), and accidental injury (18.1% vs 2.7%).

AEs including urinary tract infection and urinary retention were associated with the combination of ziconotide and anticonvulsants, but not antidepressants, compared with ziconotide alone; however, the incidence of other AEs, such as back pain and asthenia was in fact lower in patients receiving ziconotide and anticonvulsants, but not antidepressants, compared with patients receiving ziconotide alone.

“The incidence of these AEs for patients who received ziconotide and either antidepressants or anticonvulsants was generally between the incidence for patients who received both and those who received neither, with the exception of sweating, which was higher in the antidepressant but not anticonvulsant group, and urinary tract Infection, which was higher in the anticonvulsant but not antidepressant group,” the authors wrote. “Concomitant systemic medication should be considered when treating and interpreting AEs in patients receiving intrathecal ziconotide.”

Funding for this study was provided by Jazz Pharmaceuticals.

[Presentation title: Effect of Concomitant Antidepressant and Anticonvulsant Use on Adverse Events in Patients Receiving Intrathecal Ziconotide in a Long-Term Extension Study. Abstract 244]
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