08:26 AM

487 - Antidepressants for Pain, Naltrexone for Pain, Recovery Time

Take 3 – Practical Practice Pointers©

From the Literature

1)  Antidepressants for Pain Conditions


Given the side effect profiles of opioids and non-steroidal anti-inflammatory agents for treating pain, we are still on the hunt for safe and effective pharmacologic agents for pain control. Antidepressants, especially tricyclic antidepressants (TCAs) have been used in low doses for chronic pain for some time, and some serotonin-norepinephrine reuptake inhibitors have obtained an indication for fibromyalgia.

A recent “overview of systematic reviews” has examined the available literature on antidepressant medications for a comprehensive variety of pain syndromes. The review included information only on adults, and when there were two systematic reviews found on a particular condition, the authors selected for inclusion: 1) a Cochrane review over a non-Cochrane review due to methodology, and 2) the most comprehensive review. The primary outcome studied was pain, measured on any severity scale. For headaches, pain frequency was measured instead. Information on “any adverse event (AE)” and “withdrawals for AEs” were measured, instead of the variably reported individual adverse events. The authors assessed the quality of the included systematic reviews and recorded the reviews’ assessments of the quality of the evidence they summarized.

Twenty-six reviews were included in the overview. The authors noted significant industry ties for 45% of the studies included in the reviews; and in 26% of the trials, the industry influence was unclear. The pain conditions studied included: back pain, fibromyalgia, chronic tension-type headaches, postoperative pain, neuropathic pain, aromatase inhibitor-induced pain, depression + chronic pain, knee osteoarthritis, irritable bowel syndrome, functional dyspepsia, and non-cardiac chest pain. The antidepressants evaluated included SNRIs (e.g., duloxetine, venlafaxine), selective serotonin reuptake inhibitors (SSRIs, e.g., fluoxetine, sertraline), atypical antidepressants (e.g., mirtazapine and bupropion), and TCAs (e.g., amitriptyline, imipramine).

Ultimately, the review found low certainty evidence for many of the comparisons, so we won’t list those here. However, there was moderate certainty evidence that SNRIs were effective for chronic back pain, postoperative pain (mainly orthopedic surgery), fibromyalgia, and neuropathic pain. The effect sizes for these outcomes were all less than 10 points on a standardized 100-point scale. There was also moderate certainty evidence that TCAs were ineffective for functional dyspepsia. “Any adverse events” were common across antidepressant type and pain type. Withdrawals due to adverse events were greater than placebo for SNRI use in back pain, sciatica/osteoarthritis, functional dyspepsia, neuropathic pain, and fibromyalgia. For SSRI, TCA and atypical antidepressants, adverse events were greater in the reviews of dyspepsia, neuropathy, and headache.

John’s Comments:

This article noted that recent UK National Institute for Health and Care Excellence guidelines for chronic pain advised that ONLY antidepressants be used for any non-cancer-related chronic pain – no NSAIDs, no opioids. I’m not sure this review provides much support for that recommendation. Despite their relative safety, antidepressants provide only a small improvement in pain for a select number of conditions.


·       Ferreira GE, Abdel-Shaheed C, Underwood M, et al. Efficacy, safety, and tolerability of antidepressants for pain in adults: overview of systematic reviews. BMJ. 2023;380:e072415. Link


A Question From a Colleague and News from the Pharm

2)   Use of Low-dose Naltrexone (LDN) for Chronic Pain



“I’ve had a few patients ask me about the use of naltrexone for their chronic pain.  This is not something I’m familiar with.  Is this something I should be considering?”


The mu receptors are a class of receptors that neuromodulate different physiological functions, most prominently nociception, but also stress, temperature, respiration, endocrine activity, gastrointestinal activity, memory, mood, and motivation.  Because these receptors bind opioids, they are also often referred to as mu-opioid receptors (MORs).

Naltrexone is a nonselective pure mu-opioid receptor antagonist indicated by the U.S. Food and Drug Administration for the treatment of to treat both alcohol use disorder (AUD) and opioid use disorder (OUD) at a daily dose of 50-100 mg orally.  Lower doses of naltrexone (LDN) 1-5 mg daily are hypothesized to modulate the neuro-inflammatory process involving inflammatory cells.  LDN has been studied for analgesic and anti-inflammatory action in conditions such as fibromyalgia, diabetic neuropathy, Crohn’s disease, multiple sclerosis, and complex regional pain syndrome. 

What is know about the impact of LDN on pain is only in the context of smaller studies, but these do provide some insights into why this is an area of interest.

·       Diabetic neuropathy: A small study was conducted in 2021 with 67 participants with painful diabetic neuropathy.  Patients were randomized to receive either 2 mg naltrexone or 10 mg amitriptyline daily.  Naltrexone had similar efficacy and a superior safety profile compared with amitriptyline in diabetic neuropathy after 6 weeks of treatment. The most common side effect of naltrexone was diarrhea.1  

·       Fibromyalgia: In a small double-blind placebo-controlled crossover study conducted in 2013, LDN at a dose of LDN 4.5 mg/day was given to 31 women with a diagnosis of fibromyalgia.  It was found to reduce fibromyalgia severity by 28% compared to 18% in the placebo group.   LDN also improved mood but did not improve fatigue or sleep in these participants.

·       Complex  Regional Pain Syndrome:  The data is limited to a few case studies.  A case series of 2 patients with long-standing CRPS showed significant subjective pain relief using low-dose naltrexone within 2 months of treatment.

·       Use of LDN with opioids:  It has been postulated that since opioids have both inhibitory and excitatory actions, the selective blockade of the excitatory effects by LDN (in this case, very low dose) may paradoxically enhance opioid analgesia.  Data is limited to a few case series and small randomized-controlled trials (RCTs).  One clinical trial was conducted to test ultra-low-dose naloxone 2 or 4 mcg daily in combination with oxycodone up to 80 mg in patients with chronic low back pain.  All patients had significant pain relief compared to the placebo. The patient groups receiving naltrexone (2 or 4 mcg) had 12% lower daily opioid use compared to oxycodone alone. The result of this study should be interpreted cautiously due to the significant dropout rate.

Mark’s Comments:

While there are some data that support the efficacy and safety of LDN for several chronic pain and inflammatory disorders, there are not enough well-designed large studies demonstrating efficacy for us to feel confident about making this a routine treatment.  There are currently no guidelines for the clinical use of LDN for the treatment of chronic pain and inflammatory diseases and it is not FDA approved for this indication.  Additionally, LDN is not commercially available and must be prepared in a compounding pharmacy, making it difficult to access.  Having said that, for certain patients with unretractable pain as well as those for who have chronic pain for whom opioids would be contraindicated (such as those with a history of OUD), this may be a treatment work considering, perhaps in collaboration with a pain management subspecialist.   

Thanks to Marjan Moslemi, PharmD, MPH, one of our PGY-1 Pharmacy residents, who performed the background research and wrote the initial draft of this Pointer.


·       Substance Abuse and Mental Health Services Administration (SAMHSA).  Medications for Substance Use Disorders: Naltrexone.  Updated January 25, 2023.  Link

·       Srinivasan, A et al.  Efficacy and safety of low-dose naltrexone in painful diabetic neuropathy: A randomized, double-blind, active-control, crossover clinical trial. Journal of Diabetes.  2021: 13: 770-778.  Link

·       Younger, J et al.  (2013), Low-dose naltrexone for the treatment of fibromyalgia: Findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis & Rheumatism February 2013, 65: 529-538. Link

·        Chopra P, Cooper MS. Treatment of complex regional pain syndrome (CRPS) using low dose naltrexone (LDN). J NeuroImmune Pharmacol. 2013;8(3):470–6. Link

From PeerRxMed ( www.PeerRxMed.org )

3)  When is Your Recovery Time?


“We live in a world that celebrates work and activity, ignores renewal and recovery, and fails to recognize that both are necessary for sustained high performance.”   Jim Loehr, PhD - The Power of Full Engagement

While I’m not proud of this fact, there is a part of me that distains “down time.”  It’s the same part of me that equates efficiency and maximizing accomplishment as the measure of effectiveness/success and too often neglects creative time and margin as “unproductive.”   Most who work in healthcare have a bit of this in us.  “Achieving”, “producing,” and “high-performance” seem to be part of the DNA of our professional lives.  And yet production without recovery leads to breakdown … of individuals, relationships, teams, and organizations. 

I’ve written previously of the importance of embracing the paradox of polarity, of looking for opportunities to incorporate ‘both/and” rather than “either/or” thinking into our lives.  In my own life I have frequently not honored this dynamic, tending to favor one side of the “paradox” over the other.  I seem to be more drawn to “gathering,” “inhaling,” and saying “yes” rather than “letting go,” “exhaling,” and saying “no,” whether it pertains to more “to dos” at work or just trying to squeeze more in my life without cutting back or stopping anything.  And when we do that enough, what was once a ‘blessing” can soon become “busy” and at some point, a “burden” which if clung to long enough can lead to “burnout.” 

In pondering this dynamic, I’m reminded of Aesop’s fable of the goose and the golden egg.  To refresh your memory, one morning a farmer finds a glittering, gold-colored egg sitting beneath his goose.  At first he thinks it is a prank, but decides to have the egg appraised just in case.  To the farmer’s amazement, the egg is pure gold!   Each morning his now prized goose continues laying the valuable eggs, and the farmer becomes extremely wealthy.  But he also becomes impatient, wanting the goose to produce more rapidly.  One day in his frustration the farmer kills the goose, hoping to get all the golden eggs at once from inside.  As we all know, he  finds nothing, and now has neither a goose nor any more golden eggs.

In a book that has greatly influenced me,  The 7 Habits of Highly Effective People, author Stephen Covey uses the lesson of this fable to provide his definition of effectiveness:  “To maintain … the balance between the golden egg (production) and the health and welfare of the goose (production capability) is often a difficult judgment call.  But I suggest it is the very essence of effectiveness.”   Covey highlights/emphasizes the importance of the dynamic of engagement and recovery in order for optimal effectiveness and consistent high performance to be achieved.   And these lessons are equally important whether we’re talking about a goose, a professional athlete, or a healthcare professional. 

This week, I encourage you to reflect as to how you are attending to the “renewal and recovery” portion of the “work and activity/renewal and recovery” dynamic, and specifically on how you are building intentional scheduled recovery time into each day and week (shorter-term recovery) and into your months and year (longer-term recovery).  This is not something encouraged by our professional culture nor by our inner “drive.”  Let’s help each other break these unhelpful patterns.  Doing so may not always be easy, but it will sure be worth it. 


Mark and John

Carilion Clinic Department of Family and Community Medicine

Feel free to forward Take 3 to your colleagues. Glad to add them to the distribution list.

Email: mhgreenawald@carilionclinic.org