Antidepressants in Pain Management for Endometriosis

Utilizing medications typically prescribed for depression to manage pain may seem unconventional initially. However, research and reports suggest that antidepressants can indeed offer pain relief. But does this hold true for alleviating endometriosis-related pain, and which specific antidepressants are employed? Today, we will explore everything you need to understand about using antidepressants in endometriosis therapy.

The Connection Between Pain and Depression

Pain and depression share a significant link, according to researchers. For instance, Fishbain, a prominent researcher in the field, suggests that 25% of individuals experiencing chronic pain also grapple with major depression, a severe form of depressive disorder. Moreover, Fishbain’s analysis of 191 studies concluded that depression often follows the onset of pain rather than the other way around [1]. In the case of endometriosis patients, the prolonged experience of pain may also contribute to developing depressive symptoms. However, it is essential to note that the primary reason physicians sometimes recommend antidepressants is not solely for their mood-lifting effects. Instead, it is the pain-relieving properties, particularly of tricyclic antidepressants, that pique the interest of both healthcare providers and patients [2].

How Antidepressants Alleviate Endometriosis Pain

The pain-relieving potential of antidepressants has been recognized for decades, dating back to the 1960s when initial studies highlighted their positive impact on chronic pain. But what underlying mechanism allows drugs developed for depression to relieve pain? The central mode of action is well understood and linked to the body’s messenger substances, particularly norepinephrine and serotonin.

These messenger substances are released by nerve cells in the small junction between the nerve connections, known as the synaptic cleft. Within this synaptic cleft, the body’s own substances enhance or inhibit nerve signals by binding to specialized receptors. After fulfilling their function, the cells reabsorb these substances, causing the desired effect to diminish. This is where antidepressants come into play, as they slow down the cells’ reabsorption of these pain-inhibiting messenger substances. Consequently, the messenger substances remain active in the synaptic cleft for extended periods, effectively suppressing the transmission of pain. When the messenger substances within the synaptic cleft are more active, pain perception tends to decrease. Antidepressants extend the presence of neurotransmitters in the synaptic cleft, supporting the necessary pain relief [3], [4].

Researchers also explore additional effects of antidepressants, including:

  • Eliciting dopamine release by breaking out of pre-synaptic inhibitory D2 receptors, independently of norepinephrine and serotonin [4].
  • Nurturing nerve cells through neurotrophic effects [5].
  • Regulating synaptic plasticity, which involves the adaptation of synapses [5].
  • Producing opposing effects at the alpha1-adrenoreceptor [5].
  • Exhibiting H1-antihistaminergic effects that counteract histamine action [5].
  • Blocking sodium channels associated with pain sensation [5].
  • Enhancing the formation of nerve cells (neurogenesis) [5].
  • Displaying anticholinergic effects [5].
  • Optimizing endocrine function related to the hormone system [5].

Overview: Antidepressants Considered for Endometriosis

Are you familiar with the term “co-analgesics?” These are medications taken alongside pain relievers, commonly known as analgesics, to enhance their pain-relieving effects. Certain drugs may be considered off-label in the context of endometriosis, meaning that the medication is not officially approved for pain relief but is prescribed due to its anticipated effectiveness. Conversely, some antidepressants have received approval for pain management and are typically prescribed with other pain medications as part of a comprehensive pain management regimen.

Good to Know!

The mechanism of action of antidepressants in chronic pain remains incompletely understood, with a notable absence of evidence supporting their effectiveness in managing acute pain.

The following antidepressant agents may be suitable for addressing endometriosis-related pain:

  • Amitriptyline: Approved for treating depression and prolonged pain [6].
  • Nortriptyline: Approved for treating depression and chronic pain [6].

Opioids or anticonvulsants (anti-epileptic drugs) may also be employed to manage endometriosis.

These include:

  • Pregabalin [7]
  • Gabapentin [6]
  • Tramadol [6]
  • Tilidine/naloxone [6]
  • Morphine sulfate [6]
  • Fentanyl [6]

It is worth noting that the pain-relieving effect of antidepressants can manifest within 3–7 days, which is much quicker than the onset of their antidepressant effect, which may take up to 14 days. Interestingly, when antidepressants are utilized for pain relief, doctors typically prescribe them at lower doses than those used for treating depression [8], [3].

Various Types of Pain, Different Medications

The use of antidepressants hinges on two key factors. Firstly, the severity of the condition or pain must warrant more substantial interventions like prescribing antidepressants. Secondly, the nature of the pain also plays a crucial role, meaning that antidepressants may not be suitable for every case of persistent pain.

  1. If you exhibit signs of neuropathic pain characterized by a persistent burning sensation or sharp, shooting pains, this could indicate nerve damage. Tricyclic antidepressants or anticonvulsants may be considered [9].
  2. For individuals experiencing pain attacks, carbamazepine or oxcarbazepine may offer the most relief. These are sodium channel blockers, which fall into the category of antiepileptic drugs [9]
  3. If you are dealing with ongoing painful sensory disturbances, known as dysesthesias, medications like pregabalin or gabapentin, which are calcium channel blockers, may be beneficial. These drugs also belong to the antiepileptic class [9]

Occasionally, you may come across the mention of selectively acting antidepressants such as SNRIs and SSRIs in this context [7].

Case Study: Prescribing an Antidepressant for a 44-Year-Old Woman

Meet Marie, a 44-year-old woman who received an endometriosis diagnosis when she was 31. Alongside endometriosis lesions in her pelvic region, the condition also affected her sciatic nerve. Despite undergoing surgery, doctors could not entirely alleviate the impact on her sciatic nerve. Marie is taking progestin medication and steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen to manage her pain. However, these treatments have not provided relief from her neuropathic pain. Consequently, in consultation with her pain therapist, Marie has begun a regimen of an antidepressant containing the active ingredient amitriptyline. After several weeks, Marie reports a significant reduction in her pain levels.

Good to Know!

Nonetheless, the selection of pain relievers and complementary pain-management approaches and their combinations should always be tailored to the unique circumstances of each case. These decisions should be thoroughly discussed with the treating and prescribing physician.

Risk-Benefit Assessment: The Rational Use of Antidepressants

Antidepressants can effectively alleviate pain associated with endometriosis. However, it is crucial to conduct a comprehensive risk-benefit evaluation before prescribing antidepressants for pain management. Antidepressants are not without potential side effects, including dizziness, lightheadedness, dry mouth, and low blood pressure. Before prescribing an antidepressant, a physician will typically gather a detailed medical history to uncover contraindications that might render the medication unsuitable for you. Additionally, the physician will ensure that sensible therapeutic measures, such as hormone therapy, surgical interventions, or complementary treatments like acupuncture or physiotherapy, have already been explored. Sometimes, involving a pain therapist or psychologist in the treatment decision may be advisable. Once the decision to prescribe an antidepressant has been reached, initiating treatment with a gradual dose escalation is essential. Your doctor may also recommend regular laboratory assessments to monitor your progress [9].

In a Nutshell

Research and real-world experience indicate that antidepressants can effectively alleviate pain, including in cases of endometriosis. While various theories exist regarding their mechanism of action, the most plausible explanation is that antidepressants slow the reuptake of neurotransmitters like serotonin and norepinephrine into nerve cells, resulting in prolonged pain relief in the synaptic cleft.

It is important to note that when prescribing these medications in a pain management context, the focus is not necessarily on treating depression but their direct pain-relieving effects. However, physicians exercise caution when determining which endometriosis patients should receive such prescriptions due to potential side effects like drowsiness, fatigue, low blood pressure, and dry mouth.

In general, antidepressants are typically considered for patients who either do not benefit from or inadequately respond to conventional treatments like hormone therapy, surgery, or alternative therapies such as acupuncture. The severity of the pain also plays a crucial role in the decision-making process.

Suppose you are considering the use of an antidepressant for endometriosis-related pain. In that case, it is advisable to consult your gynecologist, who is well-equipped to guide you through this process.


  1. Fishbain DA, Cutler R, Rosomoff HL, Rosomoff RS. Chronic pain-associated depression: antecedent or consequence of chronic pain? A review. Clin J Pain. 1997 Jun;13(2):116-37. doi: 10.1097/00002508-199706000-00006. PMID: 9186019.
  2. Fishbain DA. Analgesic effects of antidepressants. J Clin Psychiatry. 2003 Jan;64(1):96; author reply 96-7. PMID: 12590632.
  3. Jurna I, Motsch J. Nichtanalgetika: Antidepressiva, Antikonvulsiva, Neuroleptika, Tranquillanzien. In: Zenz M, Jurna I (Hrsg.). Lehrbuch der Schmerztherapie. Stuttgart: Wissenschaftliche Verlagsgesellschaft, 2001:281–8.
  4. Keller C. Depression und Schmerz. Bremen: Uni-med Verlag, 2004
  5. Jasmin L, Tien D, Janni G, Ohara PT. Is noradrenaline a significant factor in the analgesic effect of antidepressants? Pain. 2003 Nov;106(1-2):3-8. doi: 10.1016/j.pain.2003.08.010. PMID: 14581104.
  6. Halis G., Kopf A., Mechsner S., Bartley J., Thode J., Ebert A.D. (2006):
    Schmerztherapeutische Optionen bei Endometriose. In: Deutsches Ärzteblatt,
    Jahrgang 103, Heft 17, A1146-A1153
  7. Willimann Patrick (2012). Multimodale Schmerztherapie bei Endometriose, In:
    Schweizer Zeitschrift für Gynäkologie 03/2012
  8. Herrath von D, Thimme W (Hrsg.). Koanalgetika bei chronischen Schmerzen. Arzneimittelbrief 2001;35:89–93.
  9. Journal für gynäkologische Endokrinologie. Medikamentöse Schmerztherapie bei Endometriose., abgerufen am 31. 03.2022.

Have you ever used antidepressants for pain management?
We welcome your insights and experiences in the comments section below.

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Dipl.-Ges.oec. Jennifer Ann Steinort