Placebos Extending Painkiller Doses

"Dose-extending placebo use is based on learning principles and schedules of reinforcement, so that conditioned stimuli acquire properties and characteristics of unconditioned stimuli," Dr Colloca told Clinical Pain Advisor.

In a review recently published in Pain, Luana Colloca, MD, PhD of the University of Maryland and colleagues advocate for the development of pain management regimens incorporating the use of “dose-extending placebos.”1

In such treatments, inert substances or subclinical doses of medication are interspersed with active treatments, in accordance with reinforcement learning principles.

“Extending the effects of a painkiller through the use of placebos may reduce side effects, decrease patient dependence and improve pain management. This novel use of placebos has the potential to change our general thinking about treatments for pain, the typical dosing for pain medications, and the ways in which treatments are evaluated,” Dr Colloca told Clinical Pain Advisor.

One hundred thousand PubMed citations on the placebo effect were screened for this review –about 1000 were considered. Twenty two of these were gathered using the search term “pharmacological conditioning.”

The review focuses on these 22 (non-) pain-related human and animal studies which showed evidence that placebos given after repeated administration of active treatments acquire medication-like effects.

Pain-related animal studies showed that contextual cues (ie, injection of saline) following pre-conditioning with analgesics (ie, morphine) enhanced tolerance to pain. Non pain-related animal studies indicated that placebos co-administered with immunosuppressants acquired immunosuppressive effects.

Pre-conditioning with analgesics may result in robust placebo responses, even with long intervals between treatments, as indicated by human pain-related studies. Human non-pain related studies showed that placebos received after pharmacological conditioning mimicked the effects of the active treatment.

The effects of dose-extending placebos included reduced leukocyte counts in patients with multiple sclerosis, antihistamine-like effects in patients with allergic rhinitis, reduced psoriasis symptoms, and the ability to lower dosing of amphetamines in children with ADHD.

 “Together, the aforementioned (and other) studies in humans and animals suggest that pharmacological conditioning of the immune system might impact the time course and severity of symptoms by harnessing placebo effects,” wrote the authors.

“Dose-extending placebo use is based on learning principles and schedules of reinforcement, so that conditioned stimuli (eg, color and shape of pills) acquire properties and characteristics of unconditioned stimuli (eg, morphine and oxycodone),” Dr Colloca told Clinical Pain Advisor.  

“Learning mechanisms are among the most powerful mechanisms to trigger the activation of endogenous modulatory systems for pain, eliciting the release of endogenous substances (eg, endorphins, endogenous opioids) that can decrease pain,” she added.

The use of placebos is both common and controversial in clinical practice. In a systematic review examining the frequency of placebo use, 17-80% of physicians and 51-100% of nurses reported that they had used ‘pure’ placebos such as sugar pills in the course of their professional careers.2

Dr Colloca and colleagues note that administration of placebo without a clear rationale or evidence of benefit and without consent or pre-authorization is ethically questionable.

She believes that placebos can be ethically integrated into clinical practice. “A pre-authorized use of dose-extending placebos would meet ethical standards for transparent disclosure and informed consent, and can potentially help introduce harnessing of placebo effects in the therapeutic pain management plans,” she told Clinical Pain Advisor.

This position is shared by the American Medical Association, which states in its code of ethics that placebos may be used for diagnosis or treatment, but only under certain conditions, which include patient consent.3

Summary and Clinical Applicability

More studies are needed before clinicians start interspersing active treatments with placebo. “As in any development process, confirmatory studies focusing on safety, feasibility, and dose reduction optimization are essential. We are working in this direction,” Dr Colloca told Clinical Pain Advisor.

Limitations and Disclosures

Dr Colloca is a consultant for Emmi Solution and received an annual lecture honorarium from Georgetown University. The remaining authors declared no conflicts of interest. This research was supported by funds from the National Institute of Dental and Craniofacial Research and the Clinical Center at the National Institutes of Health, which had no roles in the study. 

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  1. Colloca L, Enck P, DeGrazia D. Relieving pain using dose-extending placebos: a scoping review. Pain. 2016;157(8):1590-1598.
  2. Fässler M, Meissner K, Schneider A, Linde K. Frequency and circumstances of placebo use in clinical practice – a systematic review of empirical studies. BMC Med. 2010;8:15.
  3. Use of Placebo in Clinical Practice. AMA Code of Medical Ethics, 2014-15. Available at: Accessed August 16, 2016.