“The Placebo Effect”: Rethinking Pain Relief

by yaleglobalhealthreview, posted in Uncategorized

BY JOSHUA CHEN

Treating pain is a complex issue. Its subjective nature and dependence on physiological and psychological factors make treatment complex. Opium—extracted from poppy plants—was first officially recorded for medicinal purposes in the 3rd century BC. The prescription of opium as primarily a painkiller, or analgesic, wasn’t documented until the late 18th century [1]. Since then, specific compounds within the opium extract have been isolated and used to treat pain, the most common of which is morphine [2]. Opium derivatives, or opioids, were heavily prescribed until the 1980s when they began to be linked with drug addiction. Although incredibly effective at stopping pain signals in the brain, the addictive nature of opioids and abuse of opioid prescriptions led to the opioid crisis beginning in the 1990s [3]. The search for effective yet non-addictive painkillers continues.

Today, there are two general methods of treating pain. Less-severe acute pain—say a headache or sprained ankle—is often treated with nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin or ibuprofen. NSAIDs block cyclooxygenase, a specific enzyme that is used to produce prostaglandins. High levels of prostaglandins can cause inflammation, which causes pain, swelling, and fever [4]. By preventing the formation of prostaglandin, NSAIDs reduce inflammation and thereby reduce pain [5]. Acute and chronic pain is treated with stronger medications, which, in many cases, are opioids such as fentanyl or hydromorphone [6]. While highly effective at reducing pain, opioids have significant side effects, including dizziness, nausea, constipation, and respiratory depression. Their ability to induce relaxation and euphoria also makes opioids highly addictive. Using them to treat chronic pain is controversial for this very reason [7]. Opioid abuse can lead to slowed breathing, resulting in hypoxia—a condition where insufficient oxygen reaches the brain. Effects of hypoxia include coma, permanent brain damage, or even death [8]. Limitations of these current methods of pain relief have prompted significant research into the use of placebo analgesics. 

Placebos, in a broad medicinal context, are substances with no active ingredients and are generally used as the control group for trials to assess the efficacy of a drug with an active ingredient. One study looked at factors affecting the efficacy of placebo drugs in mitigating pain [9]. The placebo effect is based on the concept that the mind and body are deeply interconnected. The mental assumption that the drug will work influences the body’s physical response to the drug, regardless of the active biochemical ingredients absent from the drug. Researchers have found similar spinal cord patterns in both placebo and active drug responses. The efficacy of placebos was also linked to various social and behavioral factors. Taking placebos directly after repetitive “conditioning” doses of specific opioids such as morphine patients to experience morphine-like effects from the placebos. Physician-patient interactions were also found to influence outcome expectations and placebo efficacy. Observing other patients take and benefit from the actual drug was also found to increase the efficacy of placebos [9]. These findings suggest a type of top-down processing, in which the assumption of a placebo analgesia physically results in the reduction of the perception of pain [10]. These effects mimic the mechanisms of actual pain-relief medications. fMRI scans further support these findings by detecting the production of brain chemicals that mimic opioid molecules, bind to opioid receptors, and inhibit pain signaling pathways [9]. These scans confirm the placebo’s neurobiological basis. These findings suggest that placebos may be a useful alternative pain medication. Given the subjective nature of pain and pain relief, however, placebos offer a strong alternative. By leveraging the mind-body connection, placebos can reduce pain and improve symptoms without the adverse effects associated with opioid medications. The ethical concerns for using them, however, are many. 

The use of placebo drugs without the patient’s knowledge involves deception. While this approach can be effective, in a clinical setting, it undermines the trust of the patient and may result in medical harm. Furthermore, using a placebo without patient knowledge is a violation of the American Medical Association Code of Ethics. Using a placebo ethically, then, requires the patient’s cooperation and consent. The placebo’s efficacy relies at least partially on the patient’s belief that they are indeed receiving the active drug. If the patient is aware they are on a placebo, then, it stands to reason that the placebo would be rendered ineffective. Remarkably, despite the aforementioned limitations, placebos still have been shown to produce positive outcomes.

These placebos, called “Open-Label Placebos”, or OLPs, are administered to patients with their full knowledge and consent that the drug being administered is inert. Many patients are skeptical of OLPs. Logically, the concept seems counterintuitive—if patients are aware that a medication is inert, they might logically assume it will have no effect.  Yet the surprising effectiveness of OLPs challenges this expectation. Studies have shown that OLPs can significantly reduce symptoms in patients with chronic lower back pain, irritable bowel syndrome, and ADHD [11]. Evidence suggests that the success of the OLPs still relies on the belief that the drug works to reduce pain. In other words, trusting that the placebo will be effective—even in knowing that it is a placebo—causes it to be effective. Interestingly, even skeptical patients exhibited marked signs of improvement. This may be because outward skepticism doesn’t always align with subconscious belief; human perception often defies strict logic [11]. Compared to opioids, OLPs pose no risks of addiction, tolerance, or other side effects. For many patients, OLPs appear to be a great alternative to current pain treatment methods. 

Heavily supported applications for OLPs involve adjunctive treatment, in which OLPs are used to reduce a drug dosage or extend the effect of a stronger standard medication. The repetitive nature of many chronic pain medication regimens works as a sort of “conditioning” mechanism [9]. When opioids are replaced with OLPs, the body responds as if it were receiving the same drug as usual, mimicking the effects of opioid use but without the associated risks.11 The effectiveness of OLPs is not fully understood. Placebo efficacy is not solely dependent on the treatment itself but is heavily influenced by psychological and social factors. Different physiological traits such as empathy and optimism have been linked to variations in placebo responses, with more empathy and optimism being linked to stronger placebo responses [11]. More empathetic patients witnessing other patients being administered drugs and benefitting from them significantly correlated with stronger placebo effects. Specific single nucleotide polymorphisms have also been linked to increased susceptibility to placebo response [9]. These findings support the growing recognition of placebos as a feasible adjunct or alternative to conventional pain therapies, even if the precise mechanisms behind their effects remain unclear.

The cost of treatment also plays a significant role in placebo efficacy. In January of 2023, a group of Spanish researchers conducted a study examining how the price of a placebo drug influences its perceived efficacy.12 Their findings, although radical, are not unexpected. The finding that expensive placebos were perceived as more effective compared to cheaper ones follows the price-quality heuristic, an assumption that higher prices correlate with higher quality. This higher perceived quality can often lead to higher actual effectiveness.11 Again, this raises a critical ethical dilemma. While increasing the drug’s price may improve patient outcomes, it relies on the deception that the expensive drug is better when in reality, the similarly priced drugs are the same [11]. Pricing in OLPs is also a concern. Some patients in the Bernstein study were hesitant to pay for a placebo, as the idea of purchasing a “sugar pill” is unappealing [9]. Cost aside, OLP and general placebo evaluations remain largely positive with minimal drawbacks, suggesting placebos could serve as effective alternatives or adjuncts to current opioid medications, offering a promising solution to the ongoing pain management crisis.

Although not fully understood, placebos offer a compelling alternative to pain treatments like opioids, free from potential risks and side effects. As research continues to uncover the mechanisms behind the placebo effect and its practical applications, these inert yet powerful interventions may reshape how we approach pain relief in the future. By addressing ethical challenges and understanding the psychological and physiological mechanisms at work, placebos could play a transformative role in reducing dependency on opioids. Their ability to harness the mind-body connection makes them a promising tool in the future of pain management, offering hope for a safer and more effective approach to treating pain.

Joshua Chen is a sophomore in Saybrook College.

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References

  1. Meldrum ML. A capsule history of pain management. JAMA [Internet]. 2003 Nov 11;290(18):2470. Available from: https://doi.org/10.1001/jama.290.18.2470
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  3. Bernard SA, Chelminski PR, Ives TJ, Ranapurwala SI. Management of Pain in the United States—A brief history and implications for the opioid epidemic. Health Services Insights [Internet]. 2018 Jan 1;11. Available from: https://doi.org/10.1177/1178632918819440
  4. Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arteriosclerosis Thrombosis and Vascular Biology [Internet]. 2011 Apr 20;31(5):986–1000. Available from: https://doi.org/10.1161/atvbaha.110.207449
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  6. Ghelardini C. The pharmacological basis of opioids. Clinical Cases in Mineral and Bone Metabolism [Internet]. 2015 Jan 1; Available from: https://doi.org/10.11138/ccmbm/2015.12.3.219
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  8. Prescription Opioids DrugFacts | National Institute on Drug Abuse [Internet]. National Institute on Drug Abuse. 2023. Available from: https://nida.nih.gov/publications/drugfacts/prescription-opioids
  9. Colloca L, Grillon C. Understanding placebo and nocebo responses for pain management. Current Pain and Headache Reports [Internet]. 2014 Apr 26;18(6). Available from: https://doi.org/10.1007/s11916-014-0419-2
  10. Garland EL. Pain processing in the human nervous system. Primary Care Clinics in Office Practice [Internet]. 2012 Jul 24;39(3):561–71. Available from: https://doi.org/10.1016/j.pop.2012.06.013
  11. Bernstein MH, Fuchs N, Rosenfield M, Weiss AP, Blease C, Locher C, et al. Treating Pain with Open-Label Placebos: A Qualitative study with Post-Surgical Pain patients. Journal of Pain [Internet]. 2021 May 15;22(11):1518–29. Available from: https://doi.org/10.1016/j.jpain.2021.05.001
  12. Díaz-Lago M, Blanco F, Matute H. Expensive seems better: The price of a non-effective drug modulates its perceived efficacy. Cognitive Research Principles and Implications [Internet]. 2023 Jan 26;8(1). Available from: https://doi.org/10.1186/s41235-023-00463-4

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