10:40 AM

423 - Depression and COVID, Tramadol Safety, Emotional Bank Accounts

Take 3 – Practical Practice Pointers©

From the Literature

1) Depression and the Pandemic

The COVID-19 pandemic has been associated with a substantial increase in mental illness. Early data from the pandemic revealed that US adults reported an estimated three-fold increase in the prevalence of elevated depressive symptoms at the start of COVID-19 pandemic relative to before it (from 8.5% to 27.4%), including worsening mental health among healthcare workers. There is a substantial economic cost as well as increased morbidity and mortality associated with depression.

Previous work has shown that stressors, such as job loss, and lower social and economic status, measured for example by low income or less wealth, are associated with greater risk of depressive symptoms, both in the context of the COVID-19 pandemic and before it. Also, populations with fewer economic resources have been shown to be more likely to experience COVID-19 stressors, which, in turn, has led to a greater likelihood of reporting depressive symptoms.

This recently published study followed a nationally representative group of over 1,000 US adults over a 1-year time frame during the pandemic, reporting on elevated depressive symptoms and symptom severity from March-April 2020 (T1) to March-April 2021 (T2). The Patient Health Questionnaire-9 (PHQ-9) was used to define elevated depressive symptoms (cut-off ≥10) and depressive symptoms score (0-27). During this time elevated depression symptoms increased from 27.8% to 32.8% (P = .0016).

The study also found the following characteristics at T1 were associated with significant increases in depressive symptom scores between T1 and T2, controlling for baseline depressive symptoms: being ages 18-39 years (39 to 44%), having never been married (40 to 45%), having less than $75,000 in household income (32 to 38%), having less than $5,000 in household savings (40 to 51%), and reporting four or more COVID-19 stressors at T1 (38 to 51%).

The stressor count based on presence of: seeing family in person less, travel restrictions, death of someone close to you due to COVID-19, family or relationship problems, challenges finding childcare for your kids, feeling alone, not being able to get food due to shortages, not being able to get supplies due to shortages, losing a job, member of household losing a job, having financial problems, having difficulty paying rent, and being forced to leave campus.

The authors concluded that the impact of the COVID-19 pandemic on mental health has been ongoing and sustained at a population level. Depression disparities between persons of different income groups and stressor exposures are increasing.

Mark’s Comments:

Wow! The size of these numbers is staggering, and no surprise. As the authors noted, “The COVID-19 pandemic is different from other traumatic events in its ongoing length, in its widespread reach, and in its inequities." We’re only beginning to appreciate the extent of the “damage” being done beyond the virus itself. Studies such as this provide additional guidance as to those groups at even higher risk so that attention and resources can be directed toward them.

This also leaves me even more concerned as to how the pandemic is negatively impacting the mental and emotional health of our health care teams. Please be sure you’re not trying to navigate through this alone and reach out for help if needed.


Ettman C, et al. Persistent depressive symptoms during COVID-19: a national, population-representative, longitudinal study of US adults. The Lancet Regional Health - Americas open access October 4, 2021. Link


From the Literature

2) Concerns about Tramadol – Not as Safe as We Think?

Over the past two years, two large observational studies have been published in JAMA citing safety concerns about tramadol in comparison with other therapies for pain management. Tramadol has had a place in osteoarthritis management guidelines as an alternative to non-steroidal anti-inflammatory agents (NSAIDs) if they were ineffective or could not be used and has been considered preferable to traditional opioids.

The first study compared the associations of tramadol, four NSAIDs (naproxen, celecoxib, diclofenac or etoricoxib), and codeine with all-cause mortality after one year. It looked at over 88,000 patients from a UK general practice database. The study used propensity matching, which is quickly becoming the standard for observational studies, to ensure that the subjects are as equally matched on the known potential confounders as possible. It’s the closest thing to a randomized controlled trial in the retrospective observational study world. This study documented statistically significant hazard ratios (think relative risk) of 1.7 to 2.04 times the risk of death for subjects taking tramadol vs. one of the NSAIDs. In terms of absolute risk, per 1000 persons per year there were between 9.7 and 17 additional deaths attributed to tramadol vs. one of the NSAIDs. There was no difference between tramadol and codeine. The authors performed an additional five separate analyses to evaluate for residual confounding of the data, but the increased risk persisted.

The second study, released last month, retrospectively compared tramadol with codeine in the treatment of non-cancer pain for at least one year. The authors examined almost 370,000 patients in Spain for several outcomes, including falls, fractures, cardiovascular events, and all-cause mortality. The authors also used propensity score matching to reduce selection bias and included a comprehensive list of potential confounders to match participants. Compared to codeine, tramadol increased the risk of all-cause mortality (HR, 2.31 [95% CI, 2.08 to 2.56]); cardiovascular events (HR, 1.15 [95% CI, 1.05 to 1.27]), and fractures (HR, 1.50 [95% CI, 1.37 to 1.65]). The absolute risk difference for mortality was 7.4 per 1000 persons per year. The differences seen were a little greater with younger patients and female patients and lessened over time since the initial prescription. There was no increased risk in the other outcomes like delirium, falls and opioid abuse. These authors performed several sensitivity analyses to evaluate for residual confounding, and the risk was not significantly changed.

John’s Comments:

I was skeptical of the first study when it was published but seeing two major studies like this causes me to look harder at this issue. These studies were each well-done but are not the complete story.

To interpret findings of harm from studies like this, it’s helpful to think of the Bradford Hill criteria of causation (named after an epidemiologist). These aren’t hard and fast rules, but ideas to keep in mind. The criteria are:

  • effect size (how strong the stats are),
  • reproducibility (multiple studies that point in the same direction),
  • specificity (there is a tight association of one exposure with one outcome)
  • temporality (dose cause precede effect?),
  • dose-response (does more of the exposure lead to more outcome?),
  • plausibility (is there a mechanism of the effect?),
  • coherence (is the effect seen consistent with other knowledge?),
  • experiment (is there a controlled trial that supports?),
  • analogy (are there similar relationships with other agents?),
  • reversibility (does taking away the exposure decrease the risk of the outcome?).

The variation in findings between tramadol and codeine across studies is concerning (coherence). There’s no clear mechanism at play here (plausibility). In the first study, none of the disease-specific outcomes were statistically significantly different – just the overall mortality rate (plausibility). And both articles caution against assuming causality in the associations presented because of the possibility of residual confounding (specificity). On a practical level, for patients with several co-morbidities (HTN, CHF, CKD), there are known risks to both NSAID and opioid use and these studies do not compare tramadol to stronger narcotics like hydrocodone and oxycodone. For now, this data will cause me to think twice about choosing tramadol as a “safer alternative” for chronic, non-cancer pain, but I don’t think there is an indication to switch anyone off of tramadol yet.


  • Zeng C, Dubreuil M, LaRochelle MR, et al. Association of Tramadol With All-Cause Mortality Among Patients With Osteoarthritis. JAMA. 2019;321(10):969-982. doi:10.1001/jama.2019.1347. Link
  • Xie J, Strauss VY, Martinez-Laguna D, et al. Association of Tramadol vs Codeine Prescription Dispensation With Mortality and Other Adverse Clinical Outcomes. JAMA. 2021;326(15):1504-1515. doi:10.1001/jama.2021.15255. Link

From PeerRxMed ( www.PeerRxMed.org )

3) The Importance of Making Regular Deposits Into Your Accounts

“People don’t care how much you know until they know how much you care.” Attributed to many persons

Pause for a moment before continuing your reading and think about a conflict you are presently or have recently been involved in, whether that be with a family member, friend, or work colleague. Consider the dynamic of that conflict – both the content and the “tone.” Now, continue reading.

They called it the “magic ratio” and it was 5:1. The research in the 1970s by John Gottman, PhD and Robert Levenson, PhD found that regardless of the conflict that existed in a marital relationship, if for every negative interaction during that conflict there were five or more positive interactions, that marriage was predictably a happy and stable one. And the closer the ratio was to 1:1, the more ominous that was for the long-term health of that relationship.

Subsequent research by Marcial Losada, PhD and Barbara Fredrickson, PhD extended those findings beyond conflict and marriage, and resulted in what they called the Losada ratio for other relationships, including friendships and business teams. While their precise mathematical calculation has subsequently come into question, the pattern is consistent: A ratio of somewhere between 3-6 emotional uplifts for every emotional withdrawal is necjessary to create the conditions for thriving relationships, something that Stephen Covey, PhD famously called the “Emotional Bank Account.”

Now, stop again and consider the conflict that you brought to mind in the first paragraph. Any guesses as to what your “ratio” might be. If your experience is anything like mine, unless you are very consciously and deliberately making those positive deposits, your ratio is AT BEST 1:1, and likely even worse as to how you are thinking about that person. That doesn’t bode well for a healthy outcome to that conflict – or that relationship.

Hopefully you’re wondering how you might improve your ratio across many relationships so that you can build substantial emotional equity in your accounts. According to the Gottman Institute, a good initial guide is to create regular opportunities to positively engage (“small things often”) even as you make immediate “repairs” when perceived damage is done. This engagement includes expressing curiosity, demonstrating active listening, articulating that you have their interests as well as your own in mind, honoring their perspective, expressing appreciation, finding opportunities for agreement, empathizing and when appropriate, apologizing. And, in the case of close relationships, a bit of well-timed and appropriately sensitive humor can help as well.

But perhaps the first and most important step is to remember that regardless of the conflict, having healthy relationships with the people you spend time with regularly matters greatly, and therefore making regular life-enhancing deposits (remember, “small things often”) is likely the wisest investment you will ever make. Consider that this week as you are tempted to “go negative” in a conflict. You’ll be glad you did.


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