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Importance of Understanding Placebo and Nocebo effects in Healthy Vs. Patients with Chronic Pain


A very recent systematic review 1, in the Journal of Pain, went over the neurotransmitter systems associated with the placebo and nocebo effects in healthy humans as well as those with chronic pain. It did offer a fascinating insight.

What Was the Context?

Researchers have been interested in pain for a long time. That’s why numerous studies have been conducted involving neurotransmitters. The placebo and nocebo effects associated with pain are a big part of better understanding underlying mechanisms.

However, most of the said studies feature healthy participants who are exposed to experimental pain or are experiencing acute postoperative pain.

With a continued focus on finding a way to optimize placebo effects while minimizing nocebo effects during clinical practice, it has been deemed crucial for the neurotransmitter systems (that are involved in nocebo and placebo effects) to be directly investigated in subjects with chronic pain.

According to studies, the endogenous opioid system has been observed to be involved in the placebo effects demonstrated by healthy participants. Also, placebo effects in such subjects have been reported to involve the endocannabinoid, oxytocinergic, dopaminergic, and vasopressinergic systems, too. The CCKergic or cholecystokininergic system has shown involvement in the nocebo effects in healthy subjects.

But, it’s important to note that short-duration experimental pain or acute pain (in healthy subjects) is different from subjects with chronic pain. An intact nociceptive system for modulating pain is typically present in healthy participants.

However, chronic pain is linked to various mechanisms and complex pathophysiology that might be causing the pain. Psychological components for processing pain are usually more apparent in people with chronic pain.

That’s why it makes sense to think that the mechanisms associated with placebo effects present in healthy subjects might not necessarily be the same for subjects dealing with chronic pain.

Why Conduct Such a Review?

The current systematic review is the first to go over existing evidence pertaining to the involvement of the neurotransmitter systems in healthy subjects experiencing acute postoperative or experimental pain as well as subjects with chronic pain.

The goal was to offer an answer to how placebo effects might differ in said healthy patients and those with chronic pain.

LxH Model

What Was the Methodology?

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was followed for the methodology and reporting of the current paper. The team identified placebo studies by searching several electronic databases, namely Embase, PubMed, Scopus, as well as the Cochrane Library. The nocebo studies were identified post hoc by using the same electronic databases.

The articles were all in English. Also, the range included the earliest dates available in the databases through May 23, 2019. Take note; to be added, some of the factors involved the articles featuring studies aiming to understand the placebo and nocebo mechanisms as well as displaying statistically significant effects.

What Were the Results?

The initial search presented 1133 placebo along with 147 nocebo articles. With the duplicates removed, 505 placebo and 74 nocebo articles remained. After further exclusion, the final review included 28 placebo and 2 nocebo articles.

A total of 16 studies showed the involvement of the endogenous opioid system in a healthy subject’s placebo effects. Also, 8 studies shared how naloxone can be used to fully or partially block the placebo effects. However, 2 studies revealed that such effects, in a healthy subject, can’t be blocked with naloxone.

Furthermore, 2 studies talked about the contribution of the endocannabinoid system with regards to healthy subjects and placebo effects. A total of 2 studies had mixed results when it came to the involvement of the dopaminergic system. The same held true for the oxytocinergic system. The vasopressinergic system was said to be involved by one study. Take note; no study shared the involvement of the CCKergic system.

As for the placebo effects in those with chronic pain, two studies shared how the endogenous opioid system wasn’t involved. No studies about the endocannabinoid system and patients with chronic pain were found. The same happened for the oxytocinergic, vasopressinergic, and CCKergic systems. Two studies about the dopaminergic system showed mixed results.

Furthermore, 2 studies observed how the CCKergic system might be involved in a healthy subject’s nocebo effects. However, no studies were found talking about the involvement of the other systems.

Coming to subjects with chronic pain and nocebo effects, no studies were found.

What Does It Mean?

More research is needed to collect data about the types of neurotransmitter systems involved in placebo and nocebo effects in healthy subjects and those with chronic pain. A majority of the studies have focused on healthy patients.

And according to certain findings (as an example), the endogenous opioid system might not be involved in the placebo effects in chronic pain as it is involved in the pain experienced by healthy participants.

Furthermore, the psychological mechanisms linked to placebo effects are suggested to differ in subjects with chronic pain and in those who are healthy. This might play a role in why verbal suggestions display minor results when dealing with chronic pain when compared to the pain that’s experimental or acute postoperative. Understanding such differences in varying populations and conditions could aid in creating better ways to treat and manage pain.

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