SSRIs + NSAIDS = A Therapeutic Combo with Potential Problems

Antidepressants, especially selective serotonin reuptake inhibitors (or SSRIs), and NSAIDs (Non-steroidal Anti-inflammatory Drugs) are two classes of drugs commonly prescribed to patients with migraine disease. SSRIs, such as Fluoxetine (Prozac), Fluvoxamine (Luvox), Sertraline (Zoloft), Paroxetine (Paxil), Escitalopram (Lexapro), and/or Citalopram (Celexa), are typically prescribed as migraine preventatives – medications designed to proactively reduce the frequency and/or severity of attacks. NSAIDs, such as aspirin, ibuprofen, naproxen, and/or ketorolac, are commonly prescribed to help treat migraine pain once an attack begins. Most of us migraineurs, at some point or another, are prescribed both.

Ten year of combining drugs

My prescription therapy, for example, which has stretched more than a decade and included almost every drug kept in a neurologist and/or headache specialist’s arsenal to prevent, abort, and/or rescue me from attacks, almost always includes an SSRI and at least one NSAID. Unfortunately for patients like me, research suggests that this combination of drugs may pose risks and problems few health providers mention.

Common side effects

Stomach bleeding is an often-warned against, and commonly acknowledged, side effect of NSAID medications. Combining an NSAID with an SSRI, however, significantly increases the chances of GI bleeding, in some cases by more than doubling the risk.1 This is such a significant increase that many researchers are warning2 against the use of SSRIs in any patients at high risk for ulcers, indigestion, or upper gastrointestinal hemorrhage. One study conducted in Asia further suggests that brain bleeds also are significantly more likely to occur in patients using both forms of medication, especially in those patients who add an NSAID to an existing SSRI treatment.

Lower efficacy...

Even stranger, and perhaps more relevant to migraineurs and other chronic pain patients taking SSRIs, studies also indicate that SSRIs are less effective when combined with NSAIDs. Studies looking at the relationship indicate there may be up to a 10% drop3 in depression remission rates for patients taking both medications compared to those taking only the SSRI. (It is worth noting, that acetaminophen treatment also seems to reduce4 SSRI effectiveness, and that taking both types of pain relievers may cause an even greater decline in efficacy.)

...For reasons that are still unclear

This may be explained by an increased risk for depression in chronic pain patients – in that, depression may simply be more resistant to treatment in these patients due to the high comorbidity rates – but studies in mice and humans4 seem to indicate it is the drugs themselves causing the decline in effectiveness and not any comorbid condition. However, since these studies did not look at the effectiveness of SSRIs used for off-label purposes (like migraine prevention) when combined with NSAID treatment, the effect may be different for migraine prevention. That isn’t known at this time.

Taken together, however, these various studies seem to suggest that a migraine toolkit combining NSAIDs and SSRIs may be simultaneously reducing the effectiveness of the SSRI preventative and increasing the risk of serious side effects5 associated with the rescue NSAID medications. Considering that my ob-gyn once refused to prescribe me traditional birth control pills based on an increased risk of stroke in migraine patients with aura, it seems such risks are at least worth talking about – both by headache specialists and traditional practitioners – even if the absolute risks of bleeding and other problems are actually rather low, which they might be.

When the pros may outweigh the cons

It is important to note that these studies do not mean that we should absolutely avoid this combination of drugs. As with many drug therapy combinations, the benefits of using these two medications concurrently likely outweigh the risks for certain people. Whether you are one of those people is something only you and your doctor can decide.

Discussing your options with your doctor

There’s also some evidence that certain individual NSAIDs react differently with SSRIs6 than others, at least with regard to certain specific GI risks. Your doctor can help you decide which one, if any, might be best for you. Non-selective antidepressants, (i.e. antidepressants that are not considered SSRIs, such as tricyclic antidepressants) may also be an option for those of us needing some form of combined therapy, though the risk of brain bleeding appears to be the same across combinations. A knowledgeable specialist should be able to help you navigate the pros and cons of each combination – especially if you, like many of us migraineurs, have good reasons for using some form of both. Regardless, initiating a conversation to better improve our treatment options is always a good idea.

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This article represents the opinions, thoughts, and experiences of the author; none of this content has been paid for by any advertiser. The team does not recommend or endorse any products or treatments discussed herein. Learn more about how we maintain editorial integrity here.

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