By: Nicollette Pacheco, Staff Editor (Graphics-focused)

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Acetaminophen, an analgesic and antipyretic, has been widely used to relieve minor aches and pains since the 1950s. The drug exhibits these effects by inhibiting the enzymes COX-1 and COX-2, and acts in both the central and peripheral nervous systems.¹ While acetaminophen is currently indicated for the relief of mild fever and pain, recent studies reveal that it may relieve more than just a physical ache.² In vivo studies have shown that acetaminophen protects dopaminergic neurons against glutamate excitotoxicity and may protect hippocampal neurons in the brain from oxidative stress.³ In animal models, acetaminophen altered monoamines and synaptic plasticity in the hippocampus by acting on presynaptic serotonin receptors.³ While these studies are limited in their application to human models, they indicate possible psychological activity and serve as a solid foundation for further research on the use of acetaminophen in emotional pain.

In order to understand the basis of this developing theory, it is important to recognize the areas of the brain that are responsible for processing both physical and emotional pain. The experience of physical pain consists of two components: the sensory and the affective. The affective component relays information regarding the unpleasantness of a painful experience, such as the distress that follows after placing one’s hand on a hot stove.⁴ The brain regions associated with this component are known as the dorsal anterior cingulate (dACC) and the anterior insula (AI).⁴ It has been found that these two regions of the brain are not only associated with physical pain, but also with the emotional pain caused by social rejection, loss, and exclusion. In humans, the dACC and AI show increased activity while experiencing social rejection.^5,6 The phenomena of physical and emotional pain show an overlap of activity in these regions of the brain, suggesting that the dACC and AI respond to the overall sensation of distress.^4,6 Based on the finding that physical and emotional distress are represented by common somatosensory brain systems, researchers began to question the applicability of acetaminophen for emotional distress.

In a randomized, double-blind trial, 121 participants were studied to determine the effect of acetaminophen in emotionally painful situations. Each participant received either 1,000mg of acetaminophen or 1,000mg of sugar. The basis of the study corresponded to the Meaning-Maintenance Model, which theorizes that any violation of expectation leads to an affective response. In the test activity, subjects were prompted to write about death – an activity that is said to cause the affective response to pain. The control activity asked subjects to write about dental pain, which elicits thoughts of discomfort, but does not create the same experience of violated expectations as the test activity. Subjects were then asked to fill out the Positive and Negative Affect Schedule, a survey that identifies the state of affect an individual experiences. The control activity (dental pain) was implemented to rule out negative mood as an explanation to the reported state of affect. Reports of increased affirmation in the Affect Schedule test indicate an emotional response to the assigned activity.

The results of the study were consistent with the hypothesis that the only subjects to demonstrate increased affective response were exposed to the test activity and were given placebo. Subjects in the test group who were given acetaminophen demonstrated similar responses to those in the control group who did not experience an increased affective response at all.⁵

In another study, conducted by DeWall et al., participants were observed over a period of three weeks to measure their level of social pain. Patients were blinded and randomized to a daily dose of 1,000mg acetaminophen or placebo. Every evening, patients were instructed to use the Hurt Feelings Scale to report the amount of social pain experienced each day. This scale was chosen to quantify the experience of hurt feelings and to isolate the sensation of social exclusion from other negative emotions. Results demonstrated that the participants who were randomized to acetaminophen experienced less hurt feelings over time than those who were given the placebo.⁶

A third randomized, blinded study revealed that patients exposed to 1,000mg of acetaminophen reported less negativity and social discomfort towards decision-making, a thought process that typically causes significant psychological discomfort.⁷

Although current research on the use of acetaminophen for emotional conditions remains limited, there is a possibility that negative emotional experiences may contribute to physical pain disorders, such as fibromyalgia and somatoform disorders.⁴ Hyperactivity in the somatosensory cortex may also predispose certain individuals to a higher pain sensitivity.⁴ While more extensive research is necessary, the use of acetaminophen for emotional pain may be on the horizon for treatment of both physical and emotional distress. Recent publications in TIME magazine and on NPR radio have discussed these new findings and their application in medicine, increasing patient awareness of acetaminophen’s possible use for emotional pain. However, along with the emotional benefits seen in recent reports comes the hepatic toxicity that frequently limits the use of acetaminophen in clinical practice. As pharmacists, it is important to emphasize that the take home message of these news segments is not a definitive recommendation, but rather a hint at what is to come.

SOURCES:

1. Graham GG, Davies MJ, Day RO, Mohamudally A, Scott KF. The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings. Inflammopharmacology. 2013;21(3):201-32. doi: 10.1007/s10787-013-0172-x
2. Acetaminophen. In: Facts & Comparisons ® eAnswers Online. Publication city, State: Publisher. [Updated April 2015; Accessed May 27, 2015]. http://online.factsandcomparisons.com.jerome.stjohns.edu:81/MonoDisp.aspx?monoID=fandc-hcp10022&quick=159834%7c5&search=159834%7c5&isstemmed=True&NDCmapping=-1&fromTop=true#firstMatch.
3. Brown ES, Denniston D, Gabrielson B, Khan DA, Khanani S, Desai S. Randomized, double-blind, placebo-controlled trial of acetaminophen for preventing mood and memory effects of prednisone bursts. Allergy Asthma Proc. 2010;31(4):331-6. doi: 10.2500/aap.2010.31.3338.
4. Kross E, Berman MG, Mischel W, Smith EE, Wager TD. Social rejection shares somatosensory representations with physical pain. Proc Natl Acad Sci U S A. 2011;108(15):6270-5. doi: 10.1073/pnas.1102693108
5. Randles D, Heine SJ, Santos N. The common pain of surrealism and death: acetaminophen reduces compensatory affirmation following meaning threats. Psychol Sci. 2013;24(6):966-73. doi: 10.1177/0956797612464786
6. Dewall CN, Macdonald G, Webster GD, et al. Acetaminophen reduces social pain: behavioral and neural evidence. Psychol Sci. 2010;21(7):931-7. doi: 10.1177/0956797610374741
7. DeWall C, Chester D, White D. Can acetaminophen reduce the pain of decision-making? J Exp Soc Psychol. 2015;56(1):117-20.

Published by Rho Chi Post