Antidepressants for Pain Management: There Are More Options Than We Think

The efficacy and utilization of antidepressants for a wide variety of conditions continues to be challenged, particularly in the treatment of mood disorders and pain.^1-6 There remains confusion among both clinicians and patients regarding the role that this class of medication has in treating chronic pain conditions as well, as highlighted in a recent Cochrane review by Birkinshaw et al.⁷

While many findings in the review appear lackluster and, at first, seem to disparage use of many antidepressants in individuals with chronic pain, several outcomes continue to be overlooked. Herein, is a brief history of antidepressant use in chronic pain management, including the drug class’s underlying mechanisms of action and recent evidence on treatment outcomes. I specifically dive into several often disregarded positive outcomes that several antidepressants have shown in the treatment of distinct pain conditions.

Antidepressants in Pain Management: A Brief History

Traditional antidepressants have been studied and used in the treatment of chronic pain for decades. Originally used and evaluated for the treatment of pain because of their potential to relieve concomitant depression, a common comorbidity in chronic pain,⁸ it was soon discovered that antidepressants’ effects extended far beyond their ability to modulate mood.⁹ The tricyclic antidepressant (TCA) amitriptyline was among those first studied, showing efficacy in tension-type headaches in the early 1980s, then post-herpetic neuralgia,¹⁰ and eventually diabetic neuropathy in 1987.^8,11

Additional TCAs, including desipramine and imipramine, were subsequently found to have varying degrees of efficacy in similar pain conditions.^12-13 The TCAs were ultimately chemically optimized, which led to the creation of the selective serotonin and norepinephrine reuptake inhibitor (SNRI) class of antidepressants in the early 2000s, and their resultant role in the treatment of different types of chronic pain.

Antidepressant Mechanisms in Chronic Pain Management

Between the TCAs and SNRIs, there are specific medications within these classes that have shown efficacy and attained FDA approval for different pain conditions. However, this is not true of all antidepressants in general.

Antidepressant efficacy in pain seems to be limited to those that elicit noradrenergic activity at the neuronal level, as opposed to just effects on serotonin. This distinction was first shown by a randomized crossover study by Max et al in 1992, which compared desipramine (primarily noradrenergic effects), amitriptyline (serotonergic and noradrenergic effects), and fluoxetine [primarily serotonergic effects; a selective serotonin reuptake inhibitor (SSRI)] and found that only amitriptyline and desipramine provided significantly superior pain relief compared to placebo.¹⁴ Desipramine and amitriptyline were also the only medications found to be effective in patients with or without depression; as opposed to fluoxetine, which was only found to be beneficial in individuals with depression.¹⁴

From a mechanistic perspective, the results of this trial make sense, considering activation of alpha-2 adrenergic receptors throughout the spinal cord leads to neuropathic and nociceptive pain inhibition.¹⁵ Further, it has been shown that enhancing norepinephrine at the central nervous system level (mainly in the locus coeruleus) may improve underlying function of impaired descending inhibitor systems, thus supporting their potential in centrally sensitized pain conditions.¹⁵ Therefore, it would be logical that differences in noradrenergic activity may not only indicate differences in pain relief ability, but also in side effect profiles.

TCAs can be differentiated from their SNRI counterparts primarily based on their chemical structure and, thus, their activity at serotonin reuptake transporters (SERTs), norepinephrine reuptake transporters (NETs), and off-site receptors. Due to the tricyclic structure of TCAs, they not only inhibit SERT and NET, but also have antagonistic activity at alpha-1-adrenergic, histaminergic, cholinergic, and muscarinic receptors, thus increasing risk of many undesired side effects, which severely limits their use.¹⁶ The most common of these side effects include orthostasis, cardio arrhythmic effects, constipation, dizziness, and sedation. SNRIs, comparatively, are much more selective toward SERT and NET, and have minimal effects at off-site receptors, thereby reducing many of those same risks.

Considering, however, that all these medications increase synaptic serotonin concentrations, they all can increase the risk of serotonin-related side effects. This is why specific differences in potency and binding affinity toward NET and SERT, respectively, need to be considered when choosing between them. Because the primary mediator of analgesia from these classes of medications is their ability to modulate intraneuronal norepinephrine, theoretically, those antidepressants that have greater NET to SERT binding ratios could lead to greater analgesic effects and lower risk of serotonergic-related side effects including gastrointestinal effects, mood effects, and serotonin syndrome.¹⁶

Venlafaxine, especially at lower doses, has the greatest serotonergic activity of all SNRIs, followed by desvenlafaxine, followed by duloxetine, and finally followed by milnacipran; although all of these have greater serotonergic activity overall compared to noradrenergic activity.¹⁶ Levomilnacipran, an SNRI only studied for use in major depressive disorder, is the only SNRI that has greater noradrenergic activity compared to serotonergic effects.

Using the same thought process, SNRIs such as levomilnacipran, milnacipran, and duloxetine have the lowest risk of causing serotonin-related side effects,¹⁶ which can make them ideal for use in individuals who have had intolerances to serotonergic antidepressants in the past. Understanding these differences is also important in understanding why rotating between failed SNRIs may unlock potential benefits unseen before.

New Evidence on Antidepressant Pain Relief

Duloxetine and Milnacipran for Widespread, Neuropathic, and Musculoskeletal Pain

While there have been decades of evidence accumulated assessing the efficacy of various SNRIs and TCAs in the treatment of chronic pain, one particular review has gained substantial traction throughout the clinical community. Noted above, this Cochrane Review by Birkinshaw et al,⁷ evaluated 176 studies examining the efficacy and safety of antidepressants in three specific chronic pain conditions: fibromyalgia, neuropathic pain, and musculoskeletal pain.

Their primary outcomes included substantial (50%) pain relief, pain intensity, mood, and adverse events, while secondary outcomes included moderate pain relief (30%), physical function, sleep, and quality of life.⁷

The main conclusions focused on the SNRIs duloxetine and milnacipran.⁷ Specifically, Birkinshaw’s team noted that duloxetine was consistently the highest-ranked antidepressant with moderate to high certainty of evidence as it relates to its effects in chronic pain.⁷ Standard dose of duloxetine showed a small-moderate effect for substantial pain relief and continuous pain intensity, while milnacipran showed a “small” effect on pain intensity.⁷ Duloxetine and milnacipran were the highest-ranked antidepressants across all secondary efficacy outcomes as well.⁷

Imipramine, Venlafaxine, and Desvenlafaxine for Pain Intensity

Taking the authors’ conclusions at face value would leave one to believe that only duloxetine and milnacipran can substantially improve pain among the antidepressant class. However, there were several other antidepressants that showed significant efficacy regarding specific data points assessed.

In particular, imipramine (a TCA) and venlafaxine (high dose; SNRI) showed significant effects on the substantial pain relief endpoint, and desvenlafaxine (high dose; SNRI) and imipramine showed significant effects on reduction in pain intensity scores for the three pain conditions studied.⁷

Regarding secondary outcomes, imipramine showed significant effects on moderate pain relief, and desvenlafaxine showed significant change in patient global impression scores (by continuous forest plot).⁷ It is important to note all of this because one of the primary outcomes assessed was “substantial pain relief” which was defined as a reduction of pain by 50%. That is a rather large measure to use and is much larger than what is typically assessed during the FDA approval process for the majority of pain medications.

Furthermore, there were several limitations of the review (as is common for reviews of this magnitude). Some limitations included how the studies were classified (neuropathic pain is a vague description rather than a specific diagnosis and pathology) and how poorly the musculoskeletal grouping was defined (it would’ve been more meaningful to assess outcomes of specific nociceptive disease states: lower back pain, chronic joint pain, etc). Overlapping so many painful disease states could have skewed some of the results and lessened the potential impact these medications may have had on specific pain conditions. Further, not every antidepressant was evaluated by each specific efficacy outcome, meaning their omission from certain results does not necessarily equate to lack of efficacy.

Will Antidepressants Ultimately Find Their Place in Pain Treatment?

As noted, antidepressants are a diverse class of medications with varying mechanisms, potencies, and pharmacokinetic profiles that have been used for different pain conditions for several decades. Understanding the differences between them is essential in being able to select specific antidepressants for distinct pain conditions and individual patients.

Further, while the most recent review of clinical evidence supporting antidepressant use in specific pain conditions showed what has been perceived as “lackluster results,” there were, in fact, several antidepressants that showed statistically and clinically significant positive outcomes among the various pain conditions tested. This data is crucial to consider, as having many options with evidence-based efficacy for treating chronic pain widens the doors for patients to find a modality that provides benefit. Additional medication options ultimately allow for a more cumulative type of benefit to the individual patient, thus better outcomes long-term.