Which pain relievers are safe with Zoloft (Sertraline)?

A guide to which painkillers you can safely take with Sertraline


What is Sertraline?

Sertraline is a selective serotonin reuptake inhibitor (SSRI), which is a class of drugs that also includes Prozac and Paxil. SSRIs increase the amount of serotonin in the brain. Serotonin is a neurotransmitter responsible for sending signals between brain cells, in particular, signals associated with positive emotions. The chemical thus is vital to determining your mood and overall emotional state. 


What does Sertraline do?

Sertraline has been on the market since 1991 and at first, was sold by Pfizer as Zoloft, but today generic versions are widely available. It is one of the most commonly prescribed antidepressants in the United States and elsewhere. It is prescribed to treat depression, panic attacks, social anxiety, obsessive-compulsive disorder (OCD), and post-traumatic stress. In the United States alone there are over 35 million annual prescriptions. 

Sertraline also is prescribed as a low-dose ad-hoc treatment for premature ejaculation. When taken 4-8 hours prior to sexual activity it helps with delaying ejaculation, making sex more enjoyable for men who suffer from premature ejaculation.  It can also be prescribed as a daily medication for this purpose, and is actually more effective in treating premature ejaculation when taken daily.

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Can Sertraline (Zoloft) cause headaches? 

Yes, headaches are one of the possible side effects of sertraline, but they usually are limited to the first few weeks of treatment. Once sertraline concentrations in your body have stabilized, headaches tend to resolve. Similarly, you may experience headaches after you discontinue sertraline. These headaches also stop occurring after a few weeks. If headaches persist for longer or become more painful — either at the start or end of treatment — it’s recommended that you see a doctor.


Even when used only occasionally and in small doses, such as for treating premature ejaculation, sertraline can still cause headaches. 


What pain reliever can I take with Sertraline (Zoloft)?

Acetaminophen is the safest choice, as there are no major interactions with sertraline. Acetaminophen is an OTC drug and widely available. The most famous trade name is Tylenol. It is genrally very safe when taken at the recommended dose, but should not be taken by people who have liver problems.


Aspirin, ibuprofen (Advil, Motrin), and naproxen (Aleve) — all three drugs belong to the same family of nonsteroidal anti-inflammatory drugs (NSAIDs) — are not suitable for use with sertraline, since studies have shown that this combination of drugs can cause gastrointestinal bleeding as well as brain hemorrhage. To be fair though, the risks are minimal. For example, the risk of brain hemorrhage was found to be only 0.5 percent per year.


Acetaminophen will alleviate most headaches and even migraines, so there’s no pressing need to use NSAIDs.  Should you experience severe a headache that no pain killer seems to be able to stop, see a doctor for help, as the headache could be a symptom of another more serious issue. 



  1. Shin, Ju-Young, et al. “Risk of Intracranial Haemorrhage in Antidepressant Users with Concurrent Use of Non-Steroidal Anti-Inflammatory Drugs: Nationwide Propensity Score Matched Study.” BMJ, 14 July 2015, p. h3517,, Accessed 12 Dec. 2019.
  2. De Jong, Jeroen C. F., et al. “Combined Use of SSRIs and NSAIDs Increases the Risk of Gastrointestinal Adverse Effects.” British Journal of Clinical Pharmacology, vol. 55, no. 6, 12 May 2003, pp. 591–595, Accessed 12 Dec. 2019.


Reviewed by Dr Roy Kedem, MD

Information last reviewed 07/12/21

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