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The Use of Antidepressants in Multimodal Pain Management

The author shares clinical pearls for the use of these opioid alternatives in treating chronic pain and comorbid conditions.

For more than two decades, chronic pain was delineated from acute pain if it continued beyond the expected healing period and persisted for 90 days or beyond. During the general wide acceptance of this paradigm, treatment plans using opioids, which were effective in relieving acute pain, were applied to chronic pain management models; in many ways, this practice contributed to today’s nationwide challenges around opioid addiction and misuse.

This article focuses on the use of non-opioid medications—with a specific focus on antidepressants—as alternative options for the treatment of chronic pain. Recommendations are based on the author’s observational clinical experience; individual outcomes may vary and larger population studies are needed to demonstrate long-term efficacy.


Antidepressants in General

The world of antidepressants is diverse and the choice of an individual antidepressant for a patient needs to be based on multiple factors. For instance, some antidepressants have indirect analgesic properties while others are solely indicated for depression, anxiety, and/or obsessive compulsive disorder (OCD).

A good rule of thumb to remember is that the pain control provided by antidepressants is based mainly on their noradrenergic function. Norepinephrine reuptake inhibitors are, therefore, the widely used antidepressants in pain practice; specifically, duloxetine and milnacipran are FDA approved for pain and fibromyalgia, respectively. Additionally, venlafaxine and levomelnacipran, as well as certain atypical antidepressants such as mirtazapine, are commonly used off label. It should be noted that excess of norepinephrine is often no better than its deficiency and may, in and of itself, be associated with pain.1

The goal when using antidepressants to manage a patient’s pain is to avoid increasing or decreasing noradrenergic system activity and instead to balance that activity. A black-box warning regarding an increase in suicidal thoughts is attached to all antidepressants, however, epidemiologic studies consistently show a decrease in completed suicides for individuals who take antidepressants.2,3

Tricyclic Antidepressants (TCAs)

This ancient group of antidepressants is frequently used in pain management. Headaches, neuropathic pain, sleep disorders, OCD, and fibromyalgia are just a few common applications, and the use of topical tricyclic antidepressants (TCAs) seems to be on the rise. However, there are many safety issues and adverse effects associated with TCAs, primarily from potent anticholinergic effects. This class of medications is anti-arrhythmogenic. By slowing the heart, these drugs may cause\s QT prolongation and, therefore, may stop the heart if combined with other QT prolonging influences. For these reasons and more, the use of TCAs in the elderly may be problematic.

Amitriptyline (Elavil), a tertiary amine that is metabolized into a secondary amine nortriptyline (Pamelor), is commonly used for pain management. The latter is more noradrenergic than its predecessor; thus, it may produce fewer adverse effects. Both medications are significantly anticholinergic. While they produce pain control similar to that of serotonin norepinephrine reuptake inhibitors (SNRIs, see below), they generally are not considered first-line therapy due to potential increased anticholinergic and cardiotoxic adverse effects.4

Doxepin is among the most anticholinergic of its class and is available in a topical formulation approved for itching. As with other TCAs, doxepin is a potent sodium channel blocker, more so than lidocaine. Therefore, topical formulations of TCAs may be considered off-label for the treatment of peripheral neuropathies.5

Desipramine (Norpramin) is a secondary amine and metabolite of imipramine (Tofranil). It is powerfully noradrenergic and, in the author’s opinion, underutilized by pain practitioners. Patients may tolerate it poorly and it should probably not be the first choice TCA for pain management.6

Clinical pearls from the author's experience treating patients living in chronic pain with antidepressants for pain.

Clinical Pearls for TCA Use in Pain Management:

  • Use nortriptyline over amitriptyline.
  • Consider using topical forms of TCAs.
  • Remember that combining this class of medications with other serotonergic and noradrenergic medications may be unsafe.

Editor’s note: A summary of TCA chemistry, dose, indication, receptor specificity, and pharmacokinetics is available at http://paindr.com/wp-content/uploads/2015/08/TCA-Pain-Project.pdf


Selective Serotonin Reuptake Inhibitors (SSRIs)

This class of medications may be most beneficial for the treatment of psychiatric comorbidities, such as depression and anxiety, in patients living with chronic pain, but has relatively no specific pharmacological direct benefit on analgesia. Serotonin reuptake inhibitors (SSRIs) block nitric oxide synthesis and, by doing so, may cause sexual dysfunction (eg, erectile dysfunction or abnormal ejaculation in men, and delayed or absent orgasm in women). It has been observed in the author’s practice that, the more sexual side effects experienced in a patient who takes an SSRI, the more effective that SSRI may be for that patient’s pain. This may be because SSRI use can decrease nitric oxide in susceptible patients with an associated decrease in nociceptive signals reaching the central nervous system (CNS).

Paroxetine (Paxil) comes with one of the longer lists of adverse effects associated with SSRIs. It is contraindicated in pregnancy, may cause prolactinemia and weight gain, is sedating, and has been associated with severe withdrawal symptoms, as well as potential sexual side effects.7 Due to its short half-life, some patients may experience daily withdrawal. Paroxetine is also the strongest blocker of P-450 2D6 cytochrome enzyme, which metabolizes many psychotropic and analgesic medications. As such, it may decrease the potency of codeine, tramadol, and partially hydrocodone (prodrugs) and may increase the accumulation of oxycodone and other substrates of this enzyme. In the author’s view, use of paroxetine in pain management is problematic due to its poor fit in polypharmacy and its noted multiple adverse effects.

Fluoxetine (Prozac) is another P-450 2D6 inhibitor. With about a week-long half-life, it may linger in the body for up to six weeks. This property may be beneficial for avoiding withdrawal symptoms in a patient, but may not be desirable in the case of drug-drug interactions, such as with other medications metabolized by the 2D6 enzyme. As with many SSRIs, fluoxetine may increase anxiety on initiation, so starting as low a dose as possible is wise.

Sertraline (Zoloft) has a half-life of about 1 day. From the standpoint of the P-450 system, it is mostly benign in therapeutic doses and can be highly effective in the treatment of anxiety and depression. It is the preferred SSRI in this author’s practice.

Citalopram (Celexa) and Escitalopram (Lexapro) are relatively benign SSRIs with positive antidepressive effects and a less robust antianxiety function. Both medications are commonly used in primary care due to their ease of use in polypharmacy; however, they do not seem to add much to the treatment of pain.

Fluvoxamine (Luvox) is not ideal for pain management in the author’s view. Approved for the treatment of OCD, it is, in the author’s opinion, a solid representation of the SSRIs class and one that is often clinically utilized to treat depression and anxiety. Fluvoxamine may increase the blood levels of multiple medications (substrates of this enzyme), including methadone, buprenorphine, and fentanyl. It may also prolong the effect of caffeine by blocking P-450 1A2. Overall, this medication may offer an SSRI alternative when seeking to avoid CYP 2D^inhibition due to another interaction (see sidebar below on CYP metabosim in medication selection*).

Vilazodone (Viibryd) is a more recently introduced SSRI that, in addition to serotonin reuptake inhibition and 5HT2A receptor blockade, stimulates the 5HT1A receptor. This mechanism of action causes a decrease in serotonin flooding, cutting down on unwanted side effects, including sexual dysfunction. Unfortunately, this action also diminishes the medication’s anxiolytic properties. Based on its pharmacological properties, vilazodone is unlikely to find a prominent place in pain clinics, but its relatively benign sexual side effect profile may be worth remembering.

Vortioxetine (Trintellix) is a recent addition to the SSRI class that stretches its boundaries, adding more receptor activities. There is an ongoing debate about which group to assign this atypical SSRI. Traditionally, serotonin antagonist reuptake inhibitors (eg, trazadone and nefazodone) have some activity of norepinephrine reuptake inhibition – this drug does not. Through partial agonism of 5HT1B, it may increase acetylcholine and histamine levels; through 5HT3 antagonism, it may increase glutamate level; and through 5HT7 antagonism, it may increase acetylcholine and norepinephrine levels. All of these effects may produce positive cognitive influences, a much-needed benefit to many patients living with chronic pain. At the same time, glutamatergic activity may contradict clinical goals for the patient as pain practitioners usually pursue a decrease in NMDA activity.

Clinical Pearls on SSRI Use for Pain Management:

  • Based on a combination of properties, sertraline is the author’s SSRI of choice for pain management.
  • Avoid paroxetine.
  • Consider vortioxetine as a possible choice for treatment of pain patients with depression, especially for those with mild cognitive dysfunction.


Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

The idea that the noradrenergic effect is primarily responsible for chronic pain control may be confirmed in the wide utility of serotonin-norepinephrine reuptake inhibitors (SNRIs) for the treatment of chronic pain.8 It has been demonstrated, however, that it is not entirely the role of norepinephrine, but rather a balance between serotonin, norepinephrine, other neurotransmitters and receptor functions, that produce the inhibition of descending pain pathways as well as effects on central pain processing.8 Purely noradrenergic influences have been shown not to assist in pain control but, rather, to potentially increase pain.9

Duloxetine (Cymbalta) carries a label for the treatment of diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain. This medication has the unfortunate feature of being both a substrate and an inhibitor of P-450 2D6. As such, it inhibits its own metabolism within the first 48-hours of initiation or dosage adjustment, but this is easily overcome considering the blood levels adjust quickly. By blocking 2D6, duloxetine inhibits the conversion of codeine to its active form, morphine, but perhaps the biggest danger (as with any CYP2D6 Inhibitors outlines above) is abruptly stopping such Inhibitors, as this will cause a precipitant rise of serum morphine levels within 3 weeks or sooner. It has been the author’s experience that there is low awareness among practitioners of these effects and, therefore, duloxetine may be frequently mixed with these medications to the patient’s detriment. Other often-misused combinations involve amitriptyline and cyclobenzapril. These medications have an overlap in their mechanisms of action and, when used together, may create additional risks including serotonin syndrome.10This type of risk may be highest when combining duloxetine and tramadol or tapentadol

Venlafaxine (Effexor) is the oldest representative of this medication group. Although not specifically approved for pain, it is commonly and successfully used off-label in the management of chronic painful conditions, especially those of a neuropathic nature. It is worth noting that venlafaxine has been associated with increases in blood pressure and severe sexual adverse effects.11The medication also may cause unpleasant ithdrawal symptoms, whether stopped abruptly and even with slow discontinuation.12 It may, however, be deemed safer than duloxetine in polypharmacy.13

Desvenlafaxine (Pristiq) is more noradrenergic than its racemic mixture relative venlafaxine, but it seems to be less effective in the treatment of chronic pain.14 In the author’s view, itsrelatively benign adverse effect profile is a plus.


Table I. Receptor: Affinity ratio of key SNRI antidepressants.


5HT to NE ratio











SNRI is serotonin-norepinephrine reuptake inhibitors. Data based on References 15, 16.


Clinical Pearls for SNRI Use in Pain Management:

  • When possible, avoid combining serotoninergic medications due to risk of serotonin syndrome and possible aggravation of pain.17
  • Avoid duloxetine in polypharmacy when possible, especially with P-450 2D6 dependent medications.
  • When possible, avoid combining TCAs, SSRIs, and SNRIs, which may lead to serotonin syndrome, including seizures).


Atypical Antidepressants

Mirtazapine (Remeron) is a tetracyclic antidepressant. It works through alpha-2 antagonism and, as such, may provide a good fit for pain management. It normalizes gut motility, decreases abdominal pain, eases nausea, and helps to reduce anxiety.18 Unfortunately, the medication is sedating and weight gain is common. These effects seem to relate inversely to the dose of mirtazapine: the higher the dose, the less the sedation. This reaction likely occurs as histamine receptors are blocked with smaller doses; plus, norepinephrine action increases with dosage, gradually offsetting sedation. The ideal patient would, therefore, be an older, undernourished, anxious individual with abdominal pain. Mirtazapine is metabolized by multiple P-450 enzymes and represents little challenges in polypharmacy but caution should be exercised when prescribing this medication for patients with liver problems19 or in combination with other sedating medications.

Trazodone and serotonin antagonist reuptake inhibitor (SARI) is a weak antidepressant with a unique sedating effect and, while it has no label for the treatment of insomnia, has been widely used for sleep induction and maintenance.20Due to its long onset of action, it is recommended that trazodone be taken one hour or more before sleep to avoid morning drowsiness. Generally, the most troublesome adverse effect of this medication is priapism. Due to its non-addictive nature and benign impact in polypharmacy, trazodone remains understandably popular in pain management.

Nefazodone, another SARI, and various monoamine oxidase inhibitors (MAOIs) should be avoided in pain management unless the practitioner is intimately familiar with such medications. The latter has an inordinate number of dangerous drug interactions because of its inherent activity to block hepatic metabolism of many drugs and foods that contain neuroamines and/or tannins. Common foods that are especially problematic include: aged foods such as wine, cheese, pickles, pickled herring, smoked salmon, and more. Nefazodone has been associated with hepatic failure and MAOIs may be unsafe when used in combination with a wide variety of medications.

Clinical Pearls for Atypical Antidepressant Use for Pain Management:

  • Mirtazapine may be useful in the treatment of abdominal pain, especially in undernourished patients.
  • Trazodone offers an option for managing comorbid insomnia.



As described herein, antidepressants offer opioid alternatives for the management of certain chronic pain and comorbid conditions, especially depression, anxiety, and insomnia. These medications, however, may be under-prescribed due to a lack of awareness about their potential benefits in pain care and, most importantly, inexperience of pain practitioners in matching a specific medication to a specific patient.

It should be noted, importantly, that pharmacological treatment is only a part of potential success in managing chronic pain. The combined effort of a diverse treatment team is likely to produce the most desirable outcome in the patient. Psychiatry, psychology, physical therapy, osteopathic approaches, interventional treatments, and specialty treatments are all needed for rehabilitation and functional restoration.



*For More Information:

The Importance of CYP 450 Metabolism in Medication Selection for Optimal Pain Management

Over 80% of medications on the market presently are metabolized through the CYP P-450 enzyme system, which is present not just in the liver but in multiple other organs as well (see Guengerich, Chemical Research in Toxicology, 2008). Those enzymes may be activated or inhibited by various medication and foodstuff. They also may be biologically more or less active. Enzymes’ function is to metabolize and remove active medications (oxycodone, for instance, or fentanyl). The same enzymes do opposite to inactive medications by metabolizing them into active chemicals (codeine for instance, has to be turned into morphine (see Smith, Mayo Clin Proc, 2009) and tramadol into O-desmethyltramadol before they can control pain (see Gray, J Anaesthesiol Clin Pharmacol, 2018). Medications may be substrates (meaning they are activated or deactivated by a certain enzyme); they also may induce or inhibit different enzymes. If one medication, for example, induces an enzyme that metabolizes a second medication, a blood level of the second medication may disproportionately decrease. Carbamazepine is a well-known example of a medication that decreases the blood level of many other medications (and of itself) by inducing enzymes. Methadone, ketoconazole, and fluvoxamine are well known inhibitors of enzymes; therefore they may increase blood level of a number of medications. Hence, methadone increasing its own blood level becomes a known safety issue. In present-day medicine, it is imperative, therefore, to pay attention to not only medication’s properties but to how they play in an individual patient.*The opinions expressed here are those of the author and do not represent clinical treatment recommendations.




Last updated on: May 29, 2019
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