Mental Health Month may be over, yet the interest revolving around antidepressant efficacy continues on. In particular, antidepressant efficacy in the treatment of chronic pain is now being questioned with a study recently published in the Cochrane Library. Like other blogs written throughout Mental Health Month, including Pain – It’s All in Your Head and Gabapentin and Opioid Use Disorder: Correlation, Causation, or Callowness, our team wanted to explore this additional crucial question as it relates to mental health medications.
In this blog we dive into this new set of data, review the mechanisms certain antidepressants have on pain pathways, and determine whether antidepressant pain relief is a hoax or honesty.
Historical uses of antidepressants:
To consider the evidence of antidepressants for chronic pain, we really have to take a look back historically.
The first antidepressants developed were the mono-amine oxidase inhibitors in the early 1900s, specifically used to treat depression and other types of mood disorders. These antidepressants worked non-specifically on raising neuronal levels of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) which invariably led to mood improvement. Following the development of that class of antidepressants, and because of limitations with their use (substantial side effect profile), a new class of antidepressants was developed in the mid-1900s; the tricyclic antidepressants (TCAs). Imipramine was the first TCA approved, and worked more specifically than its monoamine oxidase inhibitor predecessors, primarily inhibiting the reuptake of 5-HT and/or NE within neuronal synapses. Several TCAs ended up being developed thereafter with varying activity on 5-HT and NE, as well as varying activity at off-site receptors (including cholinergic, alpha-adrenergic, muscarinic, etc), resulting in varying efficacy and side effect profiles.
Unfortunately, because of the substantial side effect profile of TCAs, more specific anti-depressants were developed, which eventually led to two additional classes; the selective serotonin reuptake inhibitors (SSRIs) and the selective serotonin and norepinephrine reuptake inhibitors (SNRIs). These primarily work on selectively raising intraneuronal 5-HT and/or NE levels, with having much lower off-site activity. In addition, several other atypical antidepressants have been developed, as well.
While it was anecdotally noted that certain antidepressants could allow for pain relief as early as the 1980s, it wasn’t until the 1990s that their efficacy was evaluated. The most well-known was a study by Max and colleagues (1992) that compared amitriptyline (NE + 5-HT) to desipramine (NE only) to fluoxetine (5-HT only) to placebo in the treatment of diabetic neuropathy. The amitriptyline and desipramine groups responded significantly better compared to those receiving fluoxetine or placebo in terms of pain reduction. This helped further our understanding of the role various neurotransmitters play in pain pathways. In particular, the role NE plays compared to that of 5-HT, with NE being the primary mediator of pain relief.
Since that time, there have only been a few antidepressants that have actually been approved for chronic pain conditions, including duloxetine and milnacipran, despite there being several antidepressants that work on pain pathways. Further, several of these antidepressants are often used off-label for a variety of pain conditions and are included in several types of pain guidelines as first line treatment modalities.
Antidepressant mechanisms of action for pain:
Ok, let’s take a step back for a second. History is history, but what may be even more important is understanding the mechanisms of why certain antidepressants can even work for pain conditions in the first place.
As we have noted, in the early 90s, it was found that the primary mechanism that antidepressants needed to possess to work on pain was noradrenergic activity. What has since been discovered is that increasing intra-synaptic norepinephrine activity can result in two different general scenarios.
On one hand, it can help modulate neuronal membrane potentials to stabilize them, which is thought why they can be useful in reduce neuropathic pain symptoms. On the other hand, it was discovered that enhancing noradrenergic activity through certain parts of the descending pain pathway (the dorsal horn and dorsal root ganglia) may alter and diminish descending pain signals. The latter mechanism is how it is postulated that antidepressants can help with nociceptive types of pains. It also could be a reason why duloxetine showed enough efficacy in phase III trials to attain FDA approval for chronic low back pain itself.
It is still the only antidepressant to gain such approval.
All of this finally leads us to the key question: Do antidepressants actually treat chronic pain?
Antidepressant efficacy for chronic pain:
The review conducted by Birkinshaw et al published only a few months ago (early 2023) helps explore the massive amounts of data out there.
This specific meta-analysis included a whopping 176 total studies assessing antidepressant efficacy in the treatment of several chronic pain conditions including fibromyalgia (59 studies), neuropathic pain (49 studies), and musculoskeletal pain (40 studies). Average length of each trial was 10 weeks, indicating the majority of studies measured short-term outcomes only. Several primary outcomes were included in analysis, including substantial pain relief (50%), pain intensity scores, mood, and adverse effects. Further, moderate pain relief (30%), physical function scores, sleep scores, and quality of life scores were also evaluated. The team evaluated all types of antidepressants, from TCAs to SSRIs, to everything in between.
Ok, so what the heck did they find?
The authors found that duloxetine, a SNRI (at the standard 60mg dose), showed a “small to moderate effect” for substantial pain relief and reducing continuous pain intensity (with moderate-certainty of evidence). Milnacipran (SNRI) at a standard dose of 100mg showed a “small effect” on pain intensity scores (moderate-certainty of evidence). Regarding secondary outcomes, duloxetine and milnacipran were the highest-ranked antidepressants with moderate-certainty evidence (effects were noted as small). No reliable conclusions were drawn from safety outcomes.
Based on the totality of data, the authors concluded that out of 25 different antidepressants assessed, the only antidepressants they were certain have efficacy for the treatment of chronic pain were duloxetine and milnacipran.
Great! So, we can only use duloxetine and milnacipran for pain?
NO!!
Despite the conclusions, there were several other antidepressants that showed significant efficacy regarding specific data points. In particular, imipramine (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. 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).
One massive limitation that was not detailed well in the study was that not all antidepressants were included for each endpoint (as they were using studies that had already been published). Thus, those antidepressants (such as amitriptyline, nortriptyline, etc) that did not have results for every outcome, were not evaluated in those outcomes whatsoever.
Their omission does not equate to inefficacy!
So, are antidepressants just another hoax chronic pain treatment?
NO!
In fact, we would say this meta-analysis proved the complete opposite. With very strict criteria, it showed that specific SNRI antidepressants (namely duloxetine and milnacipran) can be rather beneficial in the treatment of different types of chronic pain. Remember, the outcome of “substantial pain relief” is a larger outcome than most studies assess for when assessing pain relief efficacy (30% is the standard, they showed 50% pain relief). Even for antidepressants they did not list in their conclusions (including imipramine, desvenlafaxine, venlafaxine), there were significant findings proving their benefit; even if the confidence was lower.
Additionally, not every antidepressant was assessed at each outcome, therefore, the fact they were not included in the author’s conclusion does not necessarily mean they are ineffective as pain treatment. Finally, a more thorough breakdown of specific chronic pain conditions would have also been helpful in evaluating efficacy between antidepressants, instead of grouping them all together.
Antidepressant efficacy in chronic pain: The Bottom Line
As always, the selection of using an antidepressant for pain as part of a multimodal treatment approach comes down to patient-centered decision making. This may depend on individual risk of side effects, type of pain, drug-drug/drug-disease interactions, and other comorbid conditions that could benefit from their use (sleep, MDD, anxiety, etc).
They may be appropriate for some, but not for all.
However, overall, this meta-analysis shows that certain antidepressants have a place for some patients as an analgesic. While it is more difficult to determine its overall place in the analgesic hierarchy, the study represents a further step in cementing the efficacy of antidepressants in the treatment of chronic pain.
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