pain management: review of antidepressants

 Another systematic review assessed the role of antidepressants for pain management in adults (see pain management antidepressants BMJ2023 in dropbox, or doi.org/10.1136/

bmj‑2022‑072415) thanks to Karen Henley for bringing this to my attention

 

Details:

-- 26 systematic reviews were found in a search from 2012 to 2022, comparing any antidepressant with placebo for any pain condition in adults. These reviews included 156 unique trials and more than 25,000 participants

-- the analysis was stratified by different pain conditions (fibromyalgia, neuropathic pain, chronic tension-type headache, back pain, postoperative pain, aromatase inhibitor therapy-induced pain in breast cancer, depression and comorbid chronic pain, knee osteoarthritis, irritable bowel syndrome, functional dyspepsia, and noncardiac chest pain)

-- the classes of antidepressants included tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), monoamine oxidase inhibitors (MAOI), serotonin antagonist and reuptake inhibitors (SARI) and noradrenaline dopamine reuptake inhibitors (NDRI)

-- mean pain outcome was measured with any instrument used and reported as between group differences

 

Results:

-- conditions for which antidepressants had efficacy:

  -- SNRIs:

    -- back pain: duloxetine 60 mg (range 20-120 mg) for 13 weeks, 4 trials with 1415 participants, mean difference (MD) in pain intensity on a 0-100 scale: -5.3 (-7.3 to -3.3). Moderate certainty of evidence

    -- postoperative pain, 24 hours after surgery: duloxetine 60 mg (30-60 mg) for 3 days in 15 trials or venlafaxine 37.5 mg for 10 days in one trial, with total of 1126 participants: MD -7.3 (-12.9 to -1.7), moderate certainty of evidence

    -- fibromyalgia: duloxetine 120 mg (30-120 mg) for 12 weeks (7 trials), milnacipran 150 mg (100-200 mg) for 12 weeks (8 trials), total of 6918 patients: pain reduction of at least 50% with a relative risk of 1.4 (1.3-1.6), moderate certainty of evidence

        -- milnacipran is a relatively new SNRI that is more selective for norepinephrine reuptake than duloxetine or venlafaxine, and is approved for fibromyalgia, but not for depression treatment

    --  neuropathic pain: duloxetine 120 mg (60-120mg) for 12 weeks (8 trials), milnacipran 200 mg for 12 weeks (one trial), venlafaxine 172.5 mg (150-225mg) for 7 weeks (two trials), desvenlafaxine 400 mg for 13 weeks (one trial), total of 3010 patients: pain intensity had a mean difference of -6.8 (-8.7 to -4.8) , moderate certainty of evidence

    -- aromatase inhibitor therapy-induced pain in breast cancer: duloxetine 60 mg for 12 weeks (one trial with 255 participants): pain intensity mean difference -6.3 (-9.7 to -2.9); low certainty of evidence

  -- SSRIs:

    -- paroxetine 20 mg for 8 weeks (2 trials), fluoxetine 20 mg for 7 weeks (one trial), escitalopram 10 mg for 12 weeks (one trial), with total of 947 patients: pain intensity mean difference -5.9 (-10.1 to -1.7), low certainty of evidence

  -- TCAs:

    -- irritable bowel syndrome: amitriptyline 10 mg for 8 weeks, nortriptyline 10 mg for 8 weeks, doxepin 75 mg for 6 weeks, and desipramine 150 mg for 8 weeks (all of these had one trial, total of 184 participants): abdominal pain not improving with RR 0.6 (0.4-0.8), low certainty of evidence

    -- neuropathic pain: amitriptyline 75 mg (65-150mg) for 48 weeks (9 trials), and desipramine 200 mg  (160-250mg) for 6 weeks (3 trials), imipramine 150 mg for 4 weeks (one trial), maprotiliine 75 mg for 4 weeks (one trial), nortriptyline 100 mg for 9 weeks (one trial), with 948 participants: pain reduction at least 30%, RR 3.4 (2.1-5.5), low certainty of evidence

     -- chronic tension-type headache: amitriptyline 100 mg (50-150 mg) for 12 weeks (4 studies with 197 patients): headache frequency in days with a mean difference of -4.8 (-6.6  to -3), low certainty of evidence

-- conditions for which antidepressants were not efficacious:

    -- back pain: paroxetine 25 mg for 8 weeks, fluoxetine 16-514 ng/mL for 12 weeks

    -- fibromyalgia: fluoxetine 62.5 mg for 12 weeks, citalopram 40 mg for 12 weeks, paroxetine 20 mg for 8 weeks

    -- functional dyspepsia: venlafaxine 150 mg for 8 weeks, sertraline 50 mg for 8 weeks

    -- noncardiac chest pain: paroxetine 45 mg for 10 weeks, sertraline 200 mg for 9 weeks

  -- TCAs:

    -- functional dyspepsia: amitriptyline 37.5 mg for 10 weeks, imipramine 50 mg for 12 weeks, moderate certainty of evidence

 

Commentary:

-- chronic pain is remarkably common: one in 5 people globally have debilitating chronic pain

-- the most common sites of chronic pain are back pain, followed by headache, orofacial pain, and visceral pain (abdominal, pelvic, or genital pain)

-- non-opioid treatments are often suboptimal: acetaminophen has minimal data in the studies of chronic pain; NSAIDs do provide some relief, but have an array of significant adverse effects, especially if taken long-term

-- antidepressants have been used for many years. In Canada about 9% of all antidepressants prescribed were for pain and in Portugal 12% of people with back pain used antidepressants. Data from Canada, the US, the UK, and Taiwan have suggested that chronic pain was the most common condition leading to an antidepressant prescription, more so than depression

-- the 2021 NICE guidelines in the UK (see https://www.nice.org.uk/guidance/ng193, typically a very thoughtful and evidence-based set of recommendations) suggest an antidepressant as the main meds for pharmacological management of chronic pain: amitriptyline, citalopram, duloxetine, fluoxetine, paroxetine or sertraline) and NOT gabapentinoids or trigger point injections or NSAIDs or opioids or acetaminophen

    -- i agree about the gabapentinoids (see http://gmodestmedblogs.blogspot.com/2018/07/gabapentinoids-still-not-help-low-back.html for a slew of anti-gabapentinoid blogs)

    -- however, i have had some reasonable success with trigger point injections, if the trigger points actually are very tender, and even if pressure reproduces their reported radicular symptoms

    -- also, though amitriptyline has bubbled up to be the first choice by many clinicians, it does have pretty profound anticholinergic and other adverse effects, especially in the elderly. though there are very few comparative studies, desipramine and nortriptyline seem to work well (i usually use the latter at night if there is a sleep problem), and several studies in the current article did use desipramine

    -- other studies have found that venlafaxine, another SNRI, works quite well (also found in the above study)

    -- and, acetaminophen sometimes works....

-- overall, this study found that different antidepressants worked differently for different types of pain. for example duloxetine seemed pretty great for backpain, post-op pain, fibromyalgia and neuropathic pain, but not so good for aromatase inhibitor therapy, comorbid chronic pain, and knee osteoarthritis

-- but the real imperative is to first use nonpharmacologic interventions:

-- http://gmodestmedblogs.blogspot.com/2016/06/tai-chi-for-knee-oa-mindfulness-for.html for articles on tai chi and mindfulness

-- http://gmodestmedblogs.blogspot.com/2020/10/sciatica-early-pt-helps-longterm.html for an interesting study finding that early PT for acute sciatica is associated with less pain 1 year later; and http://gmodestmedblogs.blogspot.com/2017/04/pregabalin-did-not-help-sciatica.html where pregabalin did not help

-- http://gmodestmedblogs.blogspot.com/2017/04/home-based-cbt-for-low-back-pain.html for the effectiveness of home-based cognitive behavioral therapy for low back pain

-- http://gmodestmedblogs.blogspot.com/2018/03/group-therapy-decreases-chronic-pain.html for another on group therapy

http://gmodestmedblogs.blogspot.com/2016/03/low-back-pain-improves-with-stress.html finding that stress reduction though midfulness and CBT  helps

-- and some on meds:

-- http://gmodestmedblogs.blogspot.com/2018/03/opioids-not-better-for-chronic.html , a blog fiinding that opioids were no better than nonopioids, with reference to many other blogs arguing against using opioids

-- http://gmodestmedblogs.blogspot.com/2017/04/diabetic-peripheral-neuropathy-and-more.html for a medication comparison for diabetic neuropathy, finding that the best were duloxetine and venlafaxine, and pregabalin/gabapentin came in last.

http://gmodestmedblogs.blogspot.com/2022/05/acute-pain-anti-inflammatories-lead-to.html  this was an intriguing study that found that decreasing inflammation after acute low back (medically, including using NSAIDs, or by using cold, and other modalities) led to a higher rate of  subsequent chronic pain; but not so for acetaminophen or antidepressants.  ie, not reducing inflammation may trigger the body to heal itself better.....

Limitations:

-- systematic reviews of different meds comparing an intervention with placebo are fraught: each study has a different population with different causes and degrees of chronic pain and different comorbidities and psycho-social-cultural-demographics. so, one med may work better in some groups than others, and a simple comparison of the results of different studies may distort what would happen in a true head-to-head comparisons of a real randomized controlled trial...

    -- and comparing a couple of studies with few numbers of people to others with much larger and broader recruitment might distort comparisons (the elephant in the room...)

-- about half of the studies were drug-company sponsored, and, shockingly enough, this can influence results...

    -- one of the reasons i am against gabapentin is that there was a very positive drug-company study done many years ago that influenced many of us to prescribe gabapentin; then it was uncovered that an even larger drug-company study did not but was never printed....; and then several more recent systematic reviews did not find much benefit but lots of adverse effects

-- several of the studies were done many years ago (eg the TCA studies) and had less rigorous methodologies, so hard to compare effectiveness over time

-- it is not clear what the cutpoint should be for defining a clinically meaningful pain reduction. some researchers use 10 o ut of 100 as the cutpoint, but this is an arbitrary number, which would mean that most of the above noted benefits might not be significant. but there is no clear evidence-based cutpoint. and it might vary by the pain condition, the psychological state of the person, the amount of sleep they had the night before, whether they just had an argument with their partner.....  this article above explicitly did not comment on the clinically meaningful pain reduction cutpoint, acknowledging that there is no validated cutpoint

so, a few points:

-- the finding of differing effects of different antidepressants for different types of pain may mean that the results of studies of chronic pain were asymmetric (ie some studies had lots of people with diabetic neuropathy, others with low back pain), making it hard to draw real conclusions (ie their patients in the different studies may have been different enough that comparing the results is not valid)

    -- and, perhaps there really are actually important physiologic differences between different pains: there may really need to be very different approaches to the different pain groups. we need more rigorous studies on this.

    -- and, perhaps antidepressants really should be our first approach in those with many of the chronic pain presentations

-- we should still really push non-medical approaches to pain, since they really work for many people. and they should also be part of the overall plan in those needing meds...

geoff

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