Opioids enhance some antidepressants

Cooperative opioid and serotonergic mechanisms generate superior antidepressant-like effects in a mice model of depression | International Journal of Neuropsychopharmacology | Oxford Academic – free full text – September 2009

Perhaps this is another way that opioids help us deal with chronic pain. I know I’m more depressed when I’m having serious pain because it reminds me of all I’ve had to give up because of it. My future looks pretty grim when viewed through a thick haze of pain.

On days my pain isn’t so bad or I’ve managed to get it under control with opioid medication, I feel more hopeful about the future as I busy myself with all kinds of little tasks I cannot do when my pain is bad.

The opioid system has been implicated in the aetiology of depression, and some preclinical and clinical data suggest that opioids possess a genuine antidepressant-like effect.

This study aimed to investigate a potential antidepressant strategy combining different classes of monoaminergic compounds with the weak µ-opioid agonist codeine in the tail suspension test in mice, a paradigm aimed at screening potential antidepressants.

The results showed that codeine produced an antidepressant-like effect when administered alone, that was effectively antagonized by the opioid antagonist naloxone.  

The combination of subeffective doses of codeine with the selective serotonin reuptake inhibitors (fluoxetine or citalopram) lead to an accentuated reduction in immobility time.

In contrast, immobility time remained unchanged when codeine was combined with a noradrenaline reuptake inhibitor (desipramine) or with a noradrenaline/serotonin reuptake inhibitor (duloxetine).

Conversely, the combination with (+)-tramadol (µ-opioid agonist with serotonin reuptake inhibitor properties) produced a large decrease in the immobility time.

These data support the hypothesis that a combination of classical serotonergic antidepressants and weak opioid receptor agonists may be a helpful new strategy in the treatment of refractory depression.


Recent findings (STAR*D Study) indicate that about 63% of patients with major depressive disorder fail to respond to suitable first-line monotherapy with a selective serotonin reuptake inhibitor (SSRI).

Furthermore, when more treatment steps are required, lower acute remission rates, and higher relapse rates during the follow-up phase, are to be expected

These observations suggest that residual depressive symptoms predispose and portend a subsequent relapse in depression. This is especially relevant in long-term cases or when depression is comorbid with another illness (psychiatric or not).

For these reasons, great interest has been shown in the discovery and development of treatment augmentation strategies to improve the efficacy of antidepressants compounds.

we propose to explore a novel strategy in the treatment of experimental depression, combining opioid and monoaminergic compounds

We will attempt to take advantage of the existing knowledge of the effect of opioids and antidepressants in two closely linked illnesses, depression and pain.

For this purpose, we have examined the effect of the combination of the weak opioid codeine, an analgesic placed on step 2 of the WHO’s pain ladder, with antidepressant drugs in the tail suspension test in mice.


Effect of codeine and its interaction with opioid receptors

  • Dose–response studies were performed to assess the antidepressant-like effect of codeine in the tail suspension test (Fig. 1a).
  • Codeine (10–40 mg/kg i.p) induced a significant decrease in immobility time in a dose-related manner (one-way ANOVA: F3,36=3.44, p<0.05).
  • Dunnett’s post-hoc analysis indicated that codeine shows an antidepressant-like effect at 40 mg/kg (p<0.05).

40 mg/kg is NOT a low dose.

100 pounds is over 45 kg, which means that for such a small person, the codeine dose would be 1,800 mg.

This is in contrast to the dosage information for codeine: 15 to 60 mg every 4 to 6 hours (usual adult dose, 30 mg).  Even at the maximum of 60mg 6 times a day would only be 350mg.

Furthermore, codeine treatment did not affect either the muscular coordination in the tightrope test or locomotor activity.


The main finding of this study is that the association of opiates and 5-HT reuptake inhibitor compounds leads to the augmentation of the antidepressant-like effect in the tail suspension test in mice.

Specifically, the combination of subeffective doses of codeine plus either fluoxetine, citalopram or (+)-tramadol provoked a robust reduction in immobility time.

I don’t understand what they mean by “subeffective dose” when earlier, they stated antidepressant effects were noticeable with codeine at 40 mg/kg, which seems like a high dose to me.

In contrast, the combination with NA reuptake inhibitors or mixed compounds did not modify immobility time. In addition, the data obtained in the tail suspension test does not seem to be due to any specific locomotor impairment caused by the drug combination.

In summary, in the present study we have shown that the combination of the weak opioid receptor agonist, codeine, and 5-HT reuptake inhibitors provokes a robust reduction in immobility time in the tail suspension test.

This suggests that the combination of opioid and serotonergic mechanisms might be a new strategy for the development of antidepressant drugs for the treatment of refractory depression.

Moreover, considering the analgesic properties of opioids they could act on pain when this symptom is present as a remaining symptom in depression.

5 thoughts on “Opioids enhance some antidepressants

  1. Susan Brucks

    2009?!? Wonder what happened with the research. That was definitely a much friendly time for the treatment of chronic pain. I read an article today about a woman in Scotland that doesn’t feel pain or anxiety. They were able to identify the responsible gene and they are very optimistic about the possibilities of pain treatment.I feel confident in saying most everyone in pain would line up for that one!

    Liked by 2 people

  2. canarensis

    When I saw this, I was reminded of a study that indicated that tylenol helped relieve anxiety (https://www.psychologytoday.com/us/blog/the-superhuman-mind/201304/do-you-suffer-emotional-pain-or-anxiety-pop-tylenol) but while looking for that one, i ran across one from 2011 that indicated that OTC tylenol & NSAIDs DECREASE the effectiveness of anti-depressants (https://www.health.harvard.edu/press_releases/caution-popular-painkillers-may-interfere-with-antidepressants). I think it’s confusing evidence like this that makes some ‘laypersons’ decide that science is useless, & thus makes them more inclined to believe utterly simplistic nonsense like the current PROPaganda. They can’t grasp the fact that very complicated systems & conditions can’t be resolved simply.

    But I’ll bet the authors of this study have packed it in & are working on something completely different… imagine them going to meetings & suggesting the possible use of opioids in assisting treatment of depression; they’d get lynched.

    Liked by 1 person

  3. Pingback: Opioid Treatment Programs to Provide Suicide Care | EDS and Chronic Pain News & Info

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