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Pain and depression drugs not working? Antidepressants can interfere with opioids

Pharmacists have been long aware of the risks of combining certain pain and depression drugs. Many common antidepressants can significantly reduce the pain relief of opioid painkillers. A recent large-scale study of people who were taking antidepressants and received opioids after surgery had higher pain scores as much as eight weeks after surgery, compared to patients who received other medications. Inadequate pain control was observed among patients treated with pro-drug opioids (oxycodone, tramadol, Tylenol #3 with codeine) in combination with an SSRI.

Are people with depression doomed to suffer from pain?

People taking SSRIs to treat depression are already vulnerable, known to experience more pain, and often have trouble finding an effective treatment. The main reason for pain and certain depression drugs not working together is drug-gene-drug interaction. These medications are all metabolized by the same liver enzyme. Personalized medication management for pain and depression can help to resolve this problem.

The key lies in your DNA and liver metabolism

Over 70% of prescription medications are metabolized in the liver. They rely on the activity of genetically determined liver enzymes. The liver enzyme CYP2D6 is essential for converting pro-drug opioids (oxycodone, tramadol, and codeine) to active metabolites that deliver pain relief (hydromorphone and morphine).

CYP2D6 is also responsible for the clearance of many SSRIs, including paroxetine (Paxil), fluoxetine (Prozac), fluvoxamine (Luvox) as well as SNRIs venlafaxine (Effexor) and duloxetine (Cymbalta). The level of CYP2D6 enzyme, or how fast it metabolizes medications, is determined by your DNA.

Interactions affecting pain and depression drugs

When a person is taking both SSRI and pro-opioid medications, they compete for the same liver enzyme CYP2D6. As a result, the pro-opioids are not activated properly and are less effective. At the same time, SSRI levels in the blood are elevated, increasing the risks of side effects. This is a prime example of a drug-gene-drug interaction. In this case, one drug is blocking the activation of another drug.

If this interaction is not recognized, and the dose of opioid medication is increased in an effort to dampen pain, life-threatening events can occur. The risk is even higher if the person stops taking the SSRI or rapidly switches to another SSRI metabolized by a different enzyme. In such a scenario, if the block on the pro-drug opioid activation is suddenly released, the resulting influx of the active metabolite (morphine or hydromorphone) can lead to fatal breath suppression.

Overdose risk for ultrarapid metabolizers

Individuals with ultrarapid CYP2D6 metabolism are at high risk of a lethal opioid overdose. Other opioid medications such as hydromorphone, slow-release morphine or fentanyl formulation can achieve better pain control in the short-term after surgery. However, long-term use of these potent opioids greatly increases the risk of opioid addiction.

For people with high levels of chronic pain, gradual tapering of both SSRI and opioids and transition to different SSRI or analgesic is needed. However, the choice of analgesic and antidepressant must be guided by the person’s genetics.

Inadequate pain relief for slower metabolizers

The issue of SSRI and pro-opioid interaction is more pronounced in people with inherently reduced CYP2D6 activity due to underlying genetic variations. Intermediate CYP2D6 metabolizers have a stronger response to SSRIs, but reduced pain control with oxycodone, tramadol, and codeine. Therefore, both genetic and chemical block of the CYP2D6 enzyme explains why the pain and depression drugs are not working together.

If pain and depression drugs are not working for you, pharmacogenetic testing can reveal whether you have reduced or significantly elevated CYP2D6 activity and help to select alternative medications to improve the management of both conditions.

Not every antidepressant impacts pain relief

Sertraline (Zoloft), citalopram (Celexa), escitalopram (Cipralex) are metabolized by a different liver enzyme called CYP2C19, and therefore, do not block pro-opioids. However, up to 25% of people in North America have inherently increased CYP2C19 activity and do not respond to these medications because they are cleared too fast.

There are several antidepressants that also can be used to treat chronic pain. Tricyclic antidepressants such as amitriptyline, nortriptyline are effective for treating both pain and depression. However, these medications are not suitable for people who are ultrarapid or poor CYP2D6 or CYP2C19 metabolizers. Some SNRIs can also help to manage chronic central pain. Desvenlafaxine is one SNRI that is not dependent on CYP2D6 activity and can be prescribed for both poor and ultrarapid CYP2D6 metabolizers.

If your pain and depression drugs are not working for you, consider getting a pharmacogenetic test such as Pillcheck. The Pillcheck medication optimization service includes a drug response test that assesses your metabolic profile for painkillers and antidepressants. Pillcheck clinical pharmacists will provide recommendations to your physician on how to adjust your medications to improve pain and depression management.


    • Frequently pain and depression drugs do not work together – your pharmacist can help to improve your treatment
    • Use of SSRIs and pro-opioids can significantly increase the risk of accidental overdose or cause severe side effects
    • Your CYP2D6 liver enzyme determines the effectiveness of both SSRIs and pro-opioids.
    • Several treatment options are available for people with reduced or significantly elevated CYP2D6 activity
    • The Pillcheck pharmacogenetic test can help your physician to optimize treatment of pain and depression

Use Pillcheck to get on the right medications and feel better sooner.

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Pillcheck is an eligible medical expense for income tax deduction and may be reimbursed through your private insurance or company benefits plan.

Selected references

Parthipan A, et al. (2019) Predicting inadequate postoperative pain management in depressed patients: A machine learning approach. PLoS ONE 14(2): e0210575.

McCance-Katz EF, et al. (2010) Drug Interactions of Clinical Importance among the Opioids, Methadone and Buprenorphine, and other Frequently Prescribed Medications: A Review Am J Addict. 2010 Jan-Feb; 19(1): 4–16.

Kozower BD et al. Pain, pain, go away: The importance of measuring patient-reported outcomes. J Thorac Cardiovasc Surg. (2017)

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