Tuesday, December 29, 2015

Social Pain Revisited: Opioids for Severe Suicidal Ideation

Does the pain of mental anguish rely on the same neural machinery as physical pain? Can we treat these dreaded ailments with the same medications? These issues have come to the fore in the field of social/cognitive/affective neuroscience.

As many readers know, Lieberman and Eisenberger (2015) recently published a controversial paper claiming that a brain region called the dorsal anterior cingulate cortex (dACC, shown above) is “selective” for pain.1 This finding fits with their long-time narrative that rejection literally “hurts” social pain is analogous to physical pain, and both are supported by activity in same regions of dACC (Eisenberger et al., 2003). Their argument is based on work by Dr. Jaak Panksepp and colleagues, who study separation distress and other affective responses in animals (Panksepp & Yovell, 2014).

Panksepp wrote The Book on Affective Neuroscience in 1998, and coined the term even earlier (Panksepp, 1992). He also wrote a Perspective piece in Science to accompany Eisenberger et al.'s 2003 paper:

We often speak about the loss of a loved one in terms of painful feelings, but it is still not clear to what extent such metaphors reflect what is actually happening in the human brain? Enter Eisenberger and colleagues ... with a bold neuroimaging experiment that seeks to discover whether the metaphor for the psychological pain of social loss is reflected in the neural circuitry of the human brain. Using functional magnetic resonance imaging (fMRI), they show that certain human brain areas that “light up” during physical pain are also activated during emotional pain induced by social exclusion [i.e., exclusion from playing a video game].

But as I've argued for years, Social Pain and Physical Pain Are Not Interchangeable. Whenever I read an article proclaiming that “the brain bases of social pain are similar to those of physical pain”, I am reminded of how phenomenologically DIFFERENT they are.

And subsequent work has demonstrated that physical pain and actual social rejection (a recent romantic break-up) do not activate the same regions of dACC (Woo et al., 2014). Furthermore, multivariate activation patterns across the entire brain can discriminate pain and rejection with high accuracy.2 

Modified from Fig. 3 (Woo et al., 2014). Differences between fMRI pattern-based classifiers for pain and rejection.

Feelings of rejection were elicited by showing the participants pictures of their ex-partners (vs. pictures of close friends), and physical pain was elicited by applying painful heat to the forearm (vs. warm heat).

Does this mean there is no overlap between brain systems that can dampen physical and emotional pain (e.g., endogenous opioids)? Of course not; otherwise those suffering from utter despair, unspeakable loneliness, and other forms of psychic turmoil would not self-medicate with mind-altering substances.

Separation Distress: Of Mice and Psychoanalysis

Although Panksepp has worked primarily with rodents and other animals throughout his career, he maintains a keen interest in neuropsychoanalysis, an attempt to merge Freudian psychoanalysis with contemporary neuroscience. Neuropsychoanalysis “seeks to understand the human mind, especially as it relates to first-person experience.” If you think that's a misguided (and impossible) quest, you might be surprised by some of the prominent neuroscientists who have signed on to this agenda (see these posts).

Prof. Panksepp is currently collaborating with Prof. Yoram Yovell, a Psychoanalyst and Neuroscientist at the Institute for the Study of Affective Neuroscience (ISAN) in Haifa. A recent review paper addresses their approach of affective modeling in animals as a way to accelerate drug development in neuropsychiatry (Panksepp & Yovell, 2014). Their view is that current models of depression, which focus on animal behaviors instead of animal emotions, have hindered new breakthroughs in treatments for depression. It’s actually a fascinating and ambitious research program:
We admit that our conceptual position may be only an empirical/ontological approximation, especially when contrasted to affective qualia in humans … but it is at least a workable empirical approach that remains much underutilized. Here we advance the view that such affective modeling can yield new medical treatments more rapidly than simply focusing on behavioral processes in animals. In sum, we propose that the neglect of affect in preclinical psychiatric modeling may be a major reason why no truly new psychiatric medicinal treatments have arisen from behavior-only preclinical modeling so far.

They propose that three key primal emotional systems3 may be critical for understanding depression: SEEKING (enthusiasm-exuberance), PANIC (psychic pain), and PLAY (joyful exuberance). If these constructs sound highly anthropormorphic when applied to rats, it's because they are!! Perhaps you'd rather “reaffirm classical behaviorist dogma (Panksepp & Yovell, 2014) and stick with more traditional notions like brain reward systems, separation distress, and 50-kHz ultrasonic vocalizations (e.g., during tickling, mating, and play) when studying rodents.

Of interest today is the PANIC system (Panksepp & Yovell, 2014), which mediates the psychic pain of separation distress (i.e. excessive sadness and grief), which can be counteracted by minimizing PANIC arousals (as with low-dose opioids).” Since low-dose opioids alleviate separation distress in animals (based on reductions in distress vocalizations), why not give them to suicidal humans suffering from psychic pain?

Well... because making strong inferences about the contents of animal minds is deeply problematic (Barrett et al., 2007). I've written about some of the problems with animal models of dread and despair. One might also question whether it's wise to give opioid drugs (even in very low doses) to severely ill people.

Low-Dose Buprenorphine for Suicidal Ideation
Recently investigators are increasingly entertaining the possibility of using ‘safe opioids’ for the treatment of depression, as well as the chronic ‘psychological pain’ that often promotes suicidal ideation. To be a ‘safe opioid’, the analgesic effects and the lethal (respiratory depression) effects of a particular opioid ligand need to be dissociated. Buprenorphine, a partial agonist at μ-opioid receptors (i.e. stimulating opioid receptors at low doses, but blocking them at high doses), is just such a drug.

Panksepp and Lovell's ideas led to a clinical trial (A Study of Nopan Treatment of Acute Suicidality) and a new paper in the American Journal of Psychiatry (Yovell et al., 2015). Nopan is sublingual buprenorphine hydrochloride 0.2 mg. At higher doses, buprenorphine is used as a treatment for opioid addiction, much like methadone.

Research on suicidal behavior is an important and tragically neglected topic, and many clinicians, organizations, and industry sponsors are reluctant to engage. So it's notable that the current study was funded by the Neuropsychoanalysis Foundation (which awards grants and sponsors the journal Neuropsychoanalysis), the Hope for Depression Research Foundation (whose Board is filled with some Heavy Hitters of Neuroscience e.g., Akil, Mayberg, McEwen, Nestler, Hen), and ISAN.

It's interesting to track some of the changes in the study protocol and description over time. The initial ClinicalTrials.gov entry (dated 2010_01_11) dropped its psychoanalytic language on 2011_05_23:
The acutely suicidal patient presents a complex and dangerous clinical dilemma. Many suicidal patients receive antidepressant medications, but the onset of action of these medications is at least three weeks, and despite their established antidepressant effect, they have not shown a clear anti-suicidal benefit. Psychoanalysts hypothesized that depression (often leading to suicidality) shares important characteristics with the psychological sequelae of object loss and separation distress. Endogenous opioids (endorphins) have been implicated in mediating social bonding and separation distress in mammals. 

On the same date, the Secondary Outcome Measure (Reduction in psychache as measured by the Holden Psychache Scale) was replaced by a more standard and non-psychoanalytic instrument, the Beck Depression Inventory (Reduction in depression as measured by the BDI). Dr. Beck conceptualized depression in a cognitive framework.

On the other hand, “psychache” (coined by suicidologist Dr. Edwin Shneidman) means “unbearable psychological pain—hurt, anguish, soreness, and aching. ... Psychache stems from thwarted or distorted psychological needs . . . every suicidal act reflects some specific unfulfilled psychological need.”  Many of these views are at odds with neuropsychiatry (Schneidman, 1993):
Depression seems to have physiological, biochemical, and probably genetic components. The use of medications in treatment is on target. [so far so good] ... Suicide, on the other hand, is a phenomenological event... It is responsive to talk therapy and to changes in the environment. Suicide is not a psychiatric disorder. Suicide is a nervous dysfunction, not a mental disease.

But 90% of suicides are in people with clinically diagnosable psychiatric disorders; anxiety, depression, impulsivity, and alcohol abuse are major risk factors. While cases of psychache would certainly benefit from talk therapy and a change in environment, pharmacological (and/or brain stimulation) treatments seem to be essential. Which is the clearly the intention of Yovell et al. (2015), or else they wouldn't have conducted a drug study.

In short, I found it curious that the focus of their clinical trial changed so much mid-stream, and that the mental anguish of the original formulation is so completely and utterly human (given its genesis from the animal literature).

In the next post, I'll cover the actual study and the background on why anyone would think low-dose opioids are a good idea in cases of treatment-resistant depression and suicidality.

Read Part 2, Opioid Drugs for Mental Anguish: Basic Research and Clinical Trials.

Further Reading

Vicodin for Social Exclusion

Suffering from the pain of social rejection? Feel better with TYLENOL®

Existential Dread of Absurd Social Psychology Studies

Does Tylenol Exert its Analgesic Effects via the Spinal Cord?

The Mental Health of Lonely Marijuana Users

Tylenol Doesn't Really Blunt Your Emotions

Of Mice and Women: Animal Models of Desire, Dread, and Despair


1 In contrast, based on years of detailed neuroanatomical and neurophysiological experiments, most neuroscientists think the dACC is a functionally heterogeneous region (e.g., Vogt et al., 1992). Shortly after the Lieberman & Eisenberger (2015) paper was published, a number of researchers expressed their vehement disagreement in blog posts: Yarkoni-1, Lieberman reply, Yarkoni-2, Shackman, Wager.

2 In contrast to these results, an earlier study by this group claimed that social rejection shares somatosensory representations with physical pain. It's always nice to see examples where scientists update their own theories based on new evidence.

3 In Panksepp's scheme, there are seven basic or primal emotions that are subcortically based and evolutionarily conserved: SEEKING, RAGE, FEAR, LUST, CARE, PANIC/GRIEF, and PLAY. Needless to say, this model has not gone unchallenged (Barrett et al., 2007; LeDoux, 2015). Barrett and colleagues have argued that emotions are not natural kinds, but rather emergent psychological events constructed from core affect (positive or negative states) and a human conceptual system for emotion.


Barrett LF, Lindquist KA, Bliss-Moreau E, Duncan S, Gendron M, Mize J, Brennan L. (2007). Of Mice and Men: Natural Kinds of Emotions in the Mammalian Brain? A Response to Panksepp and Izard. Perspect Psychol Sci. 2(3):297-312.

Eisenberger NI, Lieberman MD, Williams KD. (2003). Does rejection hurt? An FMRI study of social exclusion. Science 302:290-2.

Panksepp, J., & Yovell, Y. (2014). Preclinical Modeling of Primal Emotional Affects (SEEKING, PANIC and PLAY): Gateways to the Development of New Treatments for Depression. Psychopathology, 47 (6), 383-393. DOI: 10.1159/000366208

Shneidman ES. (1993). Suicide as psychache. J Nerv Ment Dis. 181(3):145-7.

Woo CW, Koban L, Kross E, Lindquist MA, Banich MT, Ruzic L, Andrews-Hanna JR, & Wager TD (2014). Separate neural representations for physical pain and social rejection. Nature communications, 5. PMID: 25400102

Yovell, Y., Bar, G., Mashiah, M., Baruch, Y., Briskman, I., Asherov, J., Lotan, A., Rigbi, A., & Panksepp, J. (2015). Ultra-Low-Dose Buprenorphine as a Time-Limited Treatment for Severe Suicidal Ideation: A Randomized Controlled Trial. American Journal of Psychiatry DOI: 10.1176/appi.ajp.2015.15040535

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At December 30, 2015 2:07 AM, Blogger psychemulation said...

I want to praise your keen ability for critical thinking and this is a good way to keep positive! I really do love your work on this blog. Anyway, this is gonna find its way onto a dark blog I'm working on, so Ill keep you in touch if your interested in link and a little philosophical unpacking:
This is some of the most fascinating work in neuropsychology research simply because of the connection it has with the humanities through phenomenological concerns. One benefits the analysis, a priori, in considering the vestitude of empathic concern in defining its function in theory and interpretation. Functionally, and for the sake of construing a philosophical ontology of emotional belief systems, the difference between humanitarian endeavor and academic interest means that controlling for outside influences - like the suicidality of the researcher or the depressiveness of her subjects - is a matter of using outdated modes of DSM concerns.
Eric Schwitzgebel talks of in-between beliefs, and this makes for a difficult ontology (alief aside). I would like to think that outmoded phenomenological concerns are empathically derived to a good extent, and this is a process which furthermore has a definitive historical context.
The Cliodynamics of discernment would be of a heavily western philosophical origin. And when one assumes this to be in-between belief contexts, an updated theory holds, we get a neat pattern relating to a Spartiate system of beliefs. This may seem esoteric, or merely expressive of a unique pathology/distinct ideology. But if one sees the similarities between representations as significant to affective neuroscience she can better define the ontological considerations as historically validated and in so doing, relate the primal emotions of rats and primates to the complex ones involved in suicide.
This kind of research acts also a kind of therapy, in researching and redefining broad social contexts - much like EO Wilson on ants, his interpretations weigh on the questions of human nature in the same way that the person who first called our species human first must have seen our species as being more like flies - hymenoptera.

At December 30, 2015 1:46 PM, Blogger Joseph Masters said...

Great post. A topic close to my heart.

You might be interested in this recent paper by Howe and Sullivan: http://www.ncbi.nlm.nih.gov/pubmed/24211157

I find particularly interesting their argument that for many patients with chronic pain and psychiatric comorbidity, opioids are prescribed more as a treatment for the psychiatric comorbidity than as a treatment for the pain itself. It is as if we are trying to treat these patients depression with opioids as well, even though what they really need for treatment of their depression are the things that are proven to work (antidepressants, CBT etc.)

As part of their argument, they give a nice review of the (lack of) evidence for the effectiveness of opioids as an antidepressant... I thought you might be particularly interested in this part.

At January 02, 2016 12:25 PM, Blogger The Neurocritic said...

Matthew - Thanks for your comment. I admit I had to look up Cliodynamics, but please keep me updated on your post.

Joseph - Great, that's looks like very useful and relevant paper. Thanks for sending the link.

At March 08, 2016 9:11 AM, Anonymous Anonymous said...

John A - I think the Movie Lucy, though very farfetched has some truth to it, I think man’s primordial animalistic instincts (for example fight, flight, and fear) and mans beliefs that they cannot, prevent man from reaching where we could be. Going on the belief that the Bible is correct, it states that man was created in God’s image. Throughout the bible, it talks about what man could do if he just believed, it even give example of what man was doing.

There are people all around the world that are able to do amazing things. Most of them are no different than you or I, but they don’t simply believe they can do these things they do; there was never a glimmer of doubt in their minds. The person who never played and instrument, or spoke a word, can not only play the piano with the best of them but can sing. Why, because that part of their brain was unlocked to help compensate for another. The question is how do we unlock portions of our brains. It’s like a Billion locked doors we have to open and walk through one at a time. Time brought us up to this point of roughly 20% of our brain used by most of us (I convinced some of us use almost none). Time will take us to 30%, then 40%, and so-on, until a million years from now we'll be up to 100%. But time is only a small part of it, desire is the major part, we have to truly want to unlock more of our brain, and work towards that goal by continuing to learn advance and grow.


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