Special Guest Author Keith Sakata, MD
Amelia is a 45 year old woman with fibromyalgia and recurrent major depressive disorder in partial remission (PHQ-9: 10). Her depression was fully treated with escitalopram 20mg daily for several years. She switched from escitalopram to duloxetine a year ago in an attempt to treat both her depression and pain with one medication. She experienced a mild improvement in pain based on PEG scores when taking duloxetine 90mg, but several depressive symptoms returned. She continues to suffer with widespread pain in her joints, morning stiffness, poor sleep, and low motivation, which prevent her from walking her Labrador retriever. She asks if the duloxetine can be switched to something else to better treat her pain and depression.
What medication change do you recommend to help her pain and depression?
- Switch to another SNRI like venlafaxine.
- Continue duloxetine 90mg and add gabapentin for pain.
- Switch to nortriptyline for depression and pain.
- Switch back to escitalopram 20mg for depression and add in nortriptyline for pain.
What psychiatric medications help treat pain?
Antidepressants reduce pain via two mechanisms: 1) blocking ascending pain signals in the spinal cord and brainstem, and 2) reducing pain sensitivity associated with depression (Bonilla-Jaime, 2022).
Tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are more effective than SSRIs for pain according to studies focused on neuropathic pain reduction (Jann, 2007). Antidepressants show highly variable efficacy in pain treatment, reflecting the heterogeneity in pain syndromes, drug selection, and dosing.
A 2023 Cochrane network meta-analysis of 176 RCTs (N=28,664) suggested that duloxetine 60mg/day was the only antidepressant with moderate-certainty evidence of reducing pain intensity in adults with chronic pain, with a small to moderate effect for ≥50% pain relief (OR 1.9, 95% CI 1.7–2.2; NNT=7.1). Unfortunately, most of the trials in this review excluded people with mental health conditions, thus limiting their generalizability to patients with comorbid depression or anxiety (Birkinshaw, 2023).
Another systematic review of 229 RCTs for neuropathic pain that included patients with depression and anxiety found that for >50% pain relief, TCAs (amitriptyline, nortriptyline; NNT 3.6) work better than SNRIs (venlafaxine, duloxetine, desvenlafaxine; NNT 6.4) and gabapentinoids (pregabalin, gabapentin; NNT 7-8) (Finnerup, 2015).
What medications can help both pain and depression?
SNRIs: First-line for most patients for pain, depression, and anxiety.
SNRIs are the first-line medication choice to treat both chronic pain and depression. They are less effective for neuropathic pain than the TCAs, but they have fewer side effects. In general, higher doses of SNRIs are required for pain relief.
Duloxetine (60-120 mg/day) has strong evidence in addressing both pain and major depression and is typically my first choice among the SNRIs (Pakniyat-Jahromi, 2022). In an open-label 12-week study of adults aged 65+ with comorbid chronic low back pain and major depression, 47% of patients achieved depression remission with a median dose of duloxetine 90mg daily. 100% of those with remission reported less pain. On average, pain relief started at 3 weeks, whereas depression remission took 8 weeks (Karp 2009).
Venlafaxine exerts its analgesic effects only at higher doses (>150mg/day) and carries a higher risk of blood pressure elevation than duloxetine. Both duloxetine and venlafaxine have a significant risk of withdrawal symptoms, particularly if either medication is stopped abruptly.
Milnacipran (100–200 mg/day) is another SNRI that is used for pain. It was approved by the FDA in 2009 for the treatment of fibromyalgia. A Cochrane review found that milnacipran offered 30% reduction in pain for up to 40% of patients with fibromyalgia, but there was little to no evidence that milnacipran helped neuropathic pain (Derry, 2012). Milnacipran is approved in Europe for the treatment of major depression. One of its enantiomers, levomilnacipran, is approved in the US for the treatment of major depression.
Back to Amelia: Duloxetine was a good first choice for treating both pain and depression with a lower risk of side effects than other antidepressants. However, it didn’t help her pain significantly, and it has been less effective for depression than escitalopram.
TCAs: Highly effective medications for neuropathic pain, major depression, and sleep
TCAs like amitriptyline and nortriptyline have a NNT of 3.6 for neuropathic pain relief, making them more effective than SNRIs or gabapentinoids, albeit with a higher side effect burden. TCAs are effective at somewhat lower doses for pain than for major depression. For example, the target dose of nortriptyline for pain is 50-100mg (vs 75-150mg+ for depression).
Nortriptyline is often preferred to amitriptyline for the treatment of neuropathic pain and/or major depression due to a lower incidence of adverse side effects, specifically sedation, weight gain, and anticholinergic side effects (Derry, 2015; Hooten, 2016). Amitriptyline may be preferred to nortriptyline if increased sedation benefits a patient’s sleep problems.
Nortriptyline is the active metabolite of amitriptyline and exerts mainly noradrenergic effects. The combination of nortriptyline and an SSRI like escitalopram creates an SNRI mechanistically, without increasing the risk of serotonin syndrome. SSRIs that are CYP2D6 inhibitors should be used cautiously in combination with TCAs, as they will increase TCA drug levels.
Gabapentinoids for neuropathic pain and anxiety
Pregabalin and gabapentin have a NNT 7-8 for neuropathic pain. They work by inhibiting calcium channels in the spinal cord, thereby reducing pain hypersensitivity. Pregabalin, specifically, has been robustly studied in generalized anxiety disorder (8 RCTs, n= 2145). Both gabapentin and pregabalin are used off-label for anxiety in the US. They are not helpful for depression.
Back to Amelia: Given the partial return of depression on duloxetine—previously well-controlled on escitalopram—you recommend that Amelia switch back to escitalopram from duloxetine and then start a low-dose tricyclic antidepressant like nortriptyline at bedtime to target pain and improve sleep. Nortriptyline is more likely than a gabapentinoid to help with pain, particularly if the pain has fewer neuropathic features (e.g. burning, tingling).
You explain to Amelia that the goal is to return to the antidepressant that worked best for her mood while adding in a second medication to improve her pain and sleep, thereby tailoring the regimen to her specific symptoms and past response. While you could try nortriptyline monotherapy for both depression and pain, the nortriptyline doses required to treat depression may be higher than the doses needed for pain, increasing the likelihood of side effects.
Switching to venlafaxine is not recommended, as duloxetine was not particularly helpful and the two medications share a mechanism of action. You avoid combining duloxetine with gabapentin, because the duloxetine is not working well for either depression or pain and should be stopped.
What medication change do you recommend to help Amelia’s pain and depression?
- Switch to another SNRI like venlafaxine
- Continue duloxetine 90mg and add gabapentin for pain
- Switch to nortriptyline for depression and pain
- Switch back to escitalopram 20mg for depression and add in nortriptyline for pain
Guest Author Keith Sakata, MD is a third-year psychiatry resident at UCSF.
Key Points
- SNRIs like duloxetine are the best first-line option for chronic pain and depression, with strong evidence for both conditions and a favorable side effect profile.
- Need maximum pain relief? TCAs work best. In general, choose nortriptyline over amitriptyline—it’s less sedating, less anticholinergic, and less likely to cause weight gain.
Related PsychSnaps:
“How do you get started with patients with chronic pain?” Zoë Kopp. December 2023.
“What change could reduce anxiety in a patient with partial benefit from an SNRI?” Emma Samelson-Jones, January 2023.
References:
Birkinshaw H, Friedrich CM, Cole P, Eccleston C, Serfaty M, Stewart G, White S, Moore RA, Phillippo D, Pincus T. Antidepressants for pain management in adults with chronic pain: a network meta‑analysis. Cochrane Database of Systematic Reviews. 2023, Issue 5. Art. No.: CD01682.
Bonilla‑Jaime H, Sánchez‑Salcedo JA, Estevez‑Cabrera MM, Molina‑Jiménez T, Cortes‑Altamirano JL, Alfaro‑Rodríguez A. Depression and pain: use of antidepressants. Curr Neuropharmacol. 2022;20(4):384‑402. doi:10.2174/1570159X19666211227115305.
Derry S, Gill D, Phillips T, Moore RA. Milnacipran for neuropathic pain and fibromyalgia in adults. Cochrane Database of Systematic Reviews. 2012, Issue 3. Art. No.: CD008244. doi:10.1002/14651858.CD008244.pub2. Accessed 28 April 2025.
Derry S, Wiffen PJ, Aldington D, Moore RA. Nortriptyline for neuropathic pain in adults. Cochrane Database Syst Rev. 2015;(1):CD011209. doi:10.1002/14651858.CD011209.pub2.
Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, Haanpää M, Hansson P, Jensen TS, Kamerman PR, Lund K, Moore A, Raja SN, Rice ASC, Rowbotham M, Sena E, Siddall P, Smith BH, Wallace M. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta‑analysis. Lancet Neurol. 2015;14(2):162‑173.
Fishman SM, Ballantyne JC, Rathmell JP, eds. Bonica’s Management of Pain. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2018.
Hooten WM. Chronic pain and mental health disorders: shared neural mechanisms, epidemiology, and treatment. Mayo Clin Proc. 2016;91(7):955‑970. doi:10.1016/j.mayocp.2016.04.029.
Karp JF, Weiner DK, Dew MA, et al. Duloxetine and care management treatment of older adults with comorbid major depressive disorder and chronic low back pain: results of an open‑label pilot study. Int J Geriatr Psychiatry. 2009;24(10):1094‑1100. doi:10.1002/gps.2239.
Pakniyat‑Jahromi S, Amazan R, Garrels E, et al. Treatment modalities for chronic pain in elderly patients with depression: a systematic review. Prim Care Companion CNS Disord. 2022;24(3):21r03097.
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