Does Hydrocodone affect Zoloft? (+3 risks)

In this article, we will discuss how Hydrocodone can affect Zoloft. We will also discover the benefits and side effects of taking Hydrocodone and Zoloft together. We will look into the facts that need to be considered before taking these two drugs together.

Does Hydrocodone affect Zoloft?

Hydrocodone may affect Zoloft. These drugs may interact with each other but if your healthcare provider has prescribed you, then take these drugs according to the recommendations.

Taking Hydrocodone and Zoloft together may lead to severe consequences therefore, regular monitoring of side effects is essential if you are taking this drug combination.

Pharmacokinetic interactions between Hydrocodone and Zoloft

There could be severe pharmacokinetic interactions between Hydrocodone and Zoloft. It is estimated that 65% of depressive patients suffer from pain complaints. Therefore, it is common for such patients to be prescribed opiates such as Hydrocodone for pain management along with Zoloft as an antidepressant (1).

Taking Zoloft and Hydrocodone together increases the patient’s risk of serious pharmacokinetic interactions. Hydrocodone is an opiate which is a schedule-II drug and is used as a pain reliever.

Zoloft is an SSRI antidepressant used to treat depression, obsessive-compulsive disorder, panic disorder, and other related conditions. New studies have suggested the role of Zoloft in chronic pain treatment as well.

These drugs work via the cytochrome P450 liver enzymes. Zoloft is a moderate CYP2D6 inhibitor whereas, Hydrocodone is metabolized to its active form through CYP2D6 (1).

Prior to the metabolism of Hydrocodone to its active form called Hydromorphone, it has a limited affinity for opiate receptors. Hydromorphone, the active form, is responsible for most analgesic effects of Hydrocodone (1).

However, it is suggested that CYP2D6 inhibitors such as SSRI inhibitors including Zoloft might decrease the efficacy of Hydrocodone but studies examining this interaction are still lacking and need more evidence to explain the proper interaction between Hydrocodone and Zoloft (1).

Until more theories provide a link between the interaction of Hydrocodone and Zoloft, careful monitoring must be required for pain management and the antidepressant effects of taking these medications in combination (1).

What are the risk factors of Hydrocodone and Zoloft interaction?

There could be many risk factors for Zoloft and Hydrocodone interaction. Among them, individual variability plays a significant role. The interactions, side effects, benefits, and toxicity may vary from person to person.

Age is another factor that is an important risk factor as older adults are more prone to developing sedative and inhibiting effects of these medications when taken in combination.

The dosage strength of Zoloft and Hydrocodone should be managed as high doses and prolonged use of these medications may increase adverse events.

Polypharmacy is a common risk factor that may affect the efficacy of this drug regimen. Other health conditions and the use of multiple medications might increase the risk of adverse events and other complications.

Combined potential adverse effects of Hydrocodone and Zoloft

Combined potential adverse effects due to the use of Zoloft and Hydrocodone may be exaggerated and result in synergistic effects. Hydrocodone and Zoloft may exacerbate gastrointestinal symptoms such as nausea, vomiting, and diarrhoea when taken in combination.

Alcohol consumption along with Hydrocodone and Zoloft treatment may exacerbate sedative side effects. Therefore, it should be strictly prohibited to consume alcohol and other intoxicants.

Furthermore, there is an increased chance of serotonin syndrome since both drugs affect the serotonin levels in the brain and could lead to this rare condition characterized by hallucinations, tremors, and muscle stiffness which could be fatal in some cases.

These side effects of taking Zoloft and Hydrocodone together may vary from person to person, therefore, careful monitoring is required.

Common side effects of Hydrocodone monotherapy

Some common side effects associated with Hydrocodone include (2,3):

  • Constipation
  • Dizziness
  • Lightheadedness
  • Severe respiratory depression
  • Dyspepsia
  • Hallucination

Common side effects of Zoloft monotherapy

Some common adverse effects of Zoloft monotherapy include (4):

  • Diarrhoea
  • Dizziness
  • Tremors
  • Insomnia/Somnolence
  • QT prolongation
  • Serotonin syndrome

How to ensure the safe use of Hydrocodone and Zoloft together?

To ensure safe and effective use of Zoloft and Hydrocodone in combination, always consult your healthcare provider for any potential side effects or toxicity.

Both drugs are prescription medications and, therefore, should not be taken without your doctor’s recommendations. Always follow the provided schedule and dosage to ensure the safety and efficacy of the treatment.

In case of any severe adversity, contact your doctor who should comprehend appropriate indication and toxicity management to yield excellent outcomes related to Hydrocodone and Zoloft therapy (2).

If Zoloft and Hydrocodone therapy is not working, then your doctor can change your medications and prescribe other antidepressants that elevate mood and motivation. 

Regular monitoring of the patient’s side effects and follow-up checkups should be conducted. Healthcare providers should make sure that the patient does not go into a Hydrocodone overdose (2).

All healthcare providers should work in collaboration to avoid opiate overdose and to achieve optimal outcomes with combined treatment of Zoloft and Hydrocodone.


In the above article, we have discussed the link between Hydrocodone and Zoloft and the potential risks and adverse events of using these drugs together.

We have discussed that you should consult your healthcare provider and follow their guidelines for taking Hydrocodone and Zoloft and always weigh the risks and benefits of taking these drugs in combination.

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Hoffelt C, Gross T. A review of significant pharmacokinetic drug interactions with antidepressants and their management. Ment Health Clin. 2016 Mar 8;6(1):35-41. doi: 10.9740/mhc.2016.01.035. PMID: 29955445; PMCID: PMC6009245


Cofano S, Yellon R. Hydrocodone. [Updated 2022 Oct 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from:


AHFS Patient Medication Information [Internet]. Bethesda (MD): American Society of Health-System Pharmacists, Inc.; c2019. Protriptyline; [updated 2020 Jun 24; reviewed 2018 Jul 5; cited 2020 Jul 1]; [about 5 p.]. Available from:


Singh HK, Saadabadi A. Sertraline. [Updated 2023 Feb 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from:

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