One antidepressant medication, duloxetine, out of 25 other antidepressants, showed signs of effectiveness in the management of chronic pain, based on a new Cochrane Review of 176 studies that included more than 28,000 individuals.
Depressive symptoms are common among individuals with chronic pain, and antidepressants are often prescribed off-label to manage that pain, but a meta-analysis of current antidepressants’ effectiveness for a range of chronic pain conditions was lacking, wrote Hollie Birkinshaw, PhD, of the University of Southampton, United Kingdom, and colleagues.1
Methods
In the Cochrane Review, Birkinshaw et al identified 176 RCTs assessing antidepressant efficacy among adults aged 18 years and older with chronic pain conditions, primarily fibromyalgia, neuropathic pain, or musculoskeletal pain. Studies were conducted up to January 4, 2022, and most measured short-term outcomes only. Some studies involved an antidepressant vs. placebo, others compared antidepressants to each other or at different doses, and some compared antidepressants to an active comparator.
Most of the studies included in the review involved SSRIs, SNRIs, and tricyclic antidepressants (TCAs. The most common antidepressants included in the studies were amitriptyline (43 studies), duloxetine (43 studies), and milnacipran (an SNRI; 18 studies).
The primary outcomes of the review were substantial pain relief (defined as improvement of 50% or more), pain intensity, mood, and adverse events. Secondary outcomes included moderate pain relief (defined as 30% improvement), physical function, sleep, quality of life, and patient’s impression of change (based on the Patient Global Impression of Change, PGIC).
Findings
Overall, duloxetine alone showed moderate to high certainty of evidence for meeting the primary outcome of 50% reduction in pain, and standard doses appeared equally effective as higher doses. All other antidepressants included in the study showed low certainty evidence and failed to meet the primary outcomes. However, milnacipran also demonstrated a small effect on pain intensity; mirtazapine and duloxetine had small effects on mood.
The limitations of the review included the lack of long-term data, as the average length of the included studies was 10 weeks, the researchers noted. Other limitations included the lack of safety data, and lack of data on the impact of antidepressants on patients with both depression and chronic pain, since patients with diagnosed depression and anxiety were excluded, they said.
Overall, the researchers concluded, “There is currently no reliable evidence for the long-term efficacy of any antidepressant, and no reliable evidence for the safety of antidepressants for chronic pain at any timepoint.” However, they emphasized that many individuals take antidepressants for pain, and that pain is an individual experience. “Certain drugs may work for people even while the research evidence is inconclusive or unavailable,” they noted in their paper.
Perspective
“This study serves as an important summary of antidepressant evidence when used in chronic pain,” said Jeffrey J. Bettinger, PharmD, pain management clinical pharmacist at Saratoga Hospital Medical Group, Saratoga, NY, in an interview.
“Given the fact that antidepressants (particularly SNRIs and TCAs) have been around for so long and are commonly used and recommended across the board from a pain perspective, a summation of available evidence provides good context around just how efficacious these antidepressants can be from a pain perspective,” he said.
Although Dr. Bettinger said he was not surprised by the overall findings of the review, he was slightly surprised by how the researchers seemed certain that only duloxetine and milnacipran have efficacy for the treatment of chronic pain. “Despite the conclusions, there were several other antidepressants that showed significant efficacy regarding specific data points assessed,” he said.
These fine points are worth noting because one of the primary outcomes assessed in the review was “substantial pain relief,” defined as pain reduction of 50%, Dr. Bettinger noted. “That is a rather large measure to use and much larger than what is typically assessed during the FDA approval process for the majority of pain medications,” he said.
The review has several limitations, as is always the case with review of this magnitude, Dr. Bettinger said. Limitations included how pain was classified in different studies; for instance “neuropathic pain should have been separated entirely from nociceptive sources,” he said. In addition, “it would have been more meaningful to assess outcomes of specific nociceptive disease states, such as lower back pain, chronic joint pain.”
In his opinion, “the overlapping of so many painful disease states certainly could have skewed some of the results and lessened the potential impact these meds may have 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 inefficacy,” he said.
Practical Takeaways
The key message for clinicians from the review is that every patient is an individual, and experiences pain as an individual, Dr. Bettinger said. “Therefore, while evidence-based medicine will always dictate how we treat and manage any type of patient for any type of disease state, in chronic pain, patient experience will also always dictate care,” he said.
Consequently, more options with evidence-based efficacy in treating pain allow patients to explore and potentially find some modalities that benefit them, which may eventually allow for more cumulative benefits, in pain management, he said.
Disclosure: The Cochrane Review was funded by the National Institute for Health Research (NIHR)in the United Kingdom via Cochrane Infrastructure funding to Cochrane Pain, Palliative and Supportive Care (PaPaS). A total of 146 studies included in the review disclosed funding sources, and 72 of these disclosed funding from pharmaceutical companies.
