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Jan 25

What is a placebo?

Updated: May 22





What is a placebo?


The positive effect (on symptoms, e.g., pain) due to treatment administration in a therapeutic context(1). This can be through verbal suggestion (“this treatment will ease your pain”), through social learning (“this treatment really helped with my pain”), observing others, etc.(2). Pain and nausea are particularly susceptible to the placebo effect(3). Placebo assists in explaining variation in treatment responses(2).  

 

Placebo effects are not purely psychological. There is research that has shown several neurophysiological changes occur(1-2,4). Verbal suggestion of pain relief (“this will ease your pain”) and anticipation of pain relief can activate the opioid and dopaminergic systems resulting in pain reduction(4). 


All pain treatments are partially placebo 


There are numerous pain treatments where the exact mechanism for its effect are not known, some popular examples are Panadol or even spinal manipulations(5-7). All pain treatments' effects seemed to come down to three factors: non-specific effects, contextual effects, and specific effects(3).   


  • Non-specific effects can include several effects, including fluctuation in pain (pain often fluctuates), natural history of pain (in majority of acute pains, they settle down with time), the Hawthorne effect, regression to the mean, etc.(3) 

  • Contextual effects can significantly alter pain. Pain has been shown to change based on the person’s expectations, the clinician’s friendliness, the relationship/interaction with the clinician and the environment of the treatment(3)(27).   

  • Specific effects is quite self-explanatory, this is when what the treatment is intending to do actually occurs.  

 

All these factors always occur during every treatment, we can’t separate the treatment from the context or from the natural history(4). Even surgery can be due to contextual and non-specific effects.  


This is why research is important! 


Research can come in all shapes, forms, and sizes and not all scientific research is of the same quality. And poor-quality research in the pain space is not uncommon. However, research can also be done very well. For research to figure out if a treatment is truly effective it needs to be compared to a sham/placebo treatment (fake treatment) and a control group (no intervention given)(8). An example is where ultrasound therapy is conducted on one group vs another group where the machine is turned off vs people on a waiting list. This is named a control trial. To try and reduce the risk of biased participants would be randomized and research blinded (they don’t know if they are performing the real or sham treatment). Without these and considering other factors that may influence the results, we cannot apply or use this research to improve care. 


Are you getting scammed?  


It depends. Clinicians for the vast majority of the time have the best intentions to help people. People also want clinicians to be confident and sure of their treatment. However, when it comes to pain, especially persistent pain, there is very little black and white. A lot of the time treatments are trial and error. In fact, if a clinician makes strong promises on the effect of a treatment, I would be extremely cautious!  

 

Narratives surrounding pain treatments seemed to be a huge problem for clinicians working in musculoskeletal areas. Statements, like “you are out of alignment”, “muscle X is tight/weak/dysfunction”, etc. are actually problematic and can negatively affect recovery and even contribute to disability(9-12). This is known as the nocebo effect.  


What is a nocebo effect?  


This is the opposite to a placebo effect. Where there is a negative effect (on symptoms, e.g., pain) due to treatment administration in a therapeutic context(1). 

 

This can be through different mechanisms. For example, in a study conducted in 2008 participants were told that an electrical current would pass through their head which could result in a headache. Which resulted in several reports of headaches. The only thing was that the electrical current was a sham(13). Another study found that inhaled isotonic saline may induce an asthma attack or alleviate asthma symptoms, depending on whether patients with asthma were told that they had inhaled an irritant or an effective asthma treatment(14-15).  

 

Nocebo effects can even occur on larger scales such as through the media. For example a campaign that mistakenly reported on a toxic substance in a certain area led to increased incidence of symptoms ascribed to the toxins(16).  

 

As with the placebo effect, the nocebo effect is also not completely psychological with several different physiological changes observed(2,4,17-18).  


Should you avoid all placebo’s? 


This may actually be impossible. All pain treatments include a placebo effect component(1), although sometimes only very minor(3). One study found that the placebo effect contributes to 39% of the positive effects in several conservative therapies(8). 75% of treatment effects in osteoarthritis can be attributed to the placebo effect(19), 45% in Fibromyalgia (medication)(20), for lower back pain 81% in early phase and 66%+ in persistent low back pain for manual therapy(21). Overall, the analgesic effect from pain medications is thought to be 50% attributed to expectations of pain relief(17).

 

Studies even showed that different cues (e.g., smell, taste) usually associated with analgesic can start producing a placebo(2). 




From Rossettini et al., 2018(1) 



How do you know a treatment is more effective than a placebo? 

This is extremely difficult to know. Unfortunately, healthcare professionals often do not have the time (and/or incentives) to stay up to date with research. Research has shown that low-value care is still commonly offered in clinics for various reasons(22-24).  

 

So where else can you find reliable information, Google? Tik tok? Instagram? Potentially however, you would need to be able to filter through extreme amounts of misinformation.  

 

The most solid evidence comes from peer reviewed systematic reviews with meta-analysis based on RCT’s released in renounced reputable journals. For most people that have not studied science these can be extremely difficult to interpret. Some resources where you can check the efficacy of treatments: 


 


Fun facts about the placebo effect  

Greater pain reductions are seen(25-26):  


  • With branded treatments vs non-branded  

  • Higher priced medication vs discounted medication  

  • Treatment described as “new” vs existing treatments.  

 

These are great examples that demonstrate that pain is never purely due to disease, damage or pathology and always influenced by psychological and social factors.  



References


  1. Rossettini, G., Campaci, F., Bialosky, J., Huysmans, E., Vase, L., & Carlino, E. (2023). The Biology of Placebo and Nocebo Effects on Experimental and Chronic Pain: State of the Art. Journal of clinical medicine, 12(12), 4113. https://doi.org/10.3390/jcm12124113  

  2. Colloca, L., & Barsky, A. J. (2020). Placebo and Nocebo Effects. The New England journal of medicine, 382(6), 554–561. https://doi.org/10.1056/NEJMra1907805  

  3. Saueressig, T., Owen, P. J., Pedder, H., Tagliaferri, S., Kaczorowski, S., Altrichter, A., Richard, A., Miller, C. T., Donath, L., & Belavy, D. L. (2023). The importance of context (placebo effects) in conservative interventions for musculoskeletal pain: A systematic review and meta-analysis of randomized controlled trials. European journal of pain (London, England), 10.1002/ejp.2222. Advance online publication. https://doi.org/10.1002/ejp.2222  

  4. Rossettini, G., Carlino, E. & Testa, M. Clinical relevance of contextual factors as triggers of placebo and nocebo effects in musculoskeletal pain. BMC Musculoskelet Disord 19, 27 (2018). https://doi.org/10.1186/s12891-018-1943-8  

  5. Ayoub S. S. (2021). Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action. Temperature (Austin, Tex.), 8(4), 351–371. https://doi.org/10.1080/23328940.2021.1886392  

  6. Bialosky, J. E., Bishop, M. D., Price, D. D., Robinson, M. E., & George, S. Z. (2009). The mechanisms of manual therapy in the treatment of musculoskeletal pain: a comprehensive model. Manual therapy, 14(5), 531–538. https://doi.org/10.1016/j.math.2008.09.001  

  7. Sørensen, P. W., Nim, C. G., Poulsen, E., & Juhl, C. B. (2023). Spinal Manipulative Therapy for Nonspecific Low Back Pain: Does Targeting a Specific Vertebral Level Make a Difference?: A Systematic Review WithMeta-analysis. The Journal of orthopaedic and sports physical therapy, 53(9), 529–539. https://doi.org/10.2519/jospt.2023.11962  

  8. Hohenschurz-Schmidt, D., Phalip, J., Chan, J., Gauhe, G., Soliman, N., Vollert, J., Lunde, S. J., & Vase, L. (2023). Placebo analgesia in physical and psychological interventions: Systematic review and meta-analysis of three-armed trials. European journal of pain (London, England), 10.1002/ejp.2205. Advance online publication. https://doi.org/10.1002/ejp.2205  

  9. Caneiro, J. P., Bunzli, S., & O'Sullivan, P. (2021). Beliefs about the body and pain: the critical role in musculoskeletal pain management. Brazilian journal of physical therapy, 25(1), 17–29. https://doi.org/10.1016/j.bjpt.2020.06.003  

  10. Darlow, B., Dowell, A., Baxter, G. D., Mathieson, F., Perry, M., & Dean, S. (2013). The enduring impact of what clinicians say to people with low back pain. Annals of family medicine, 11(6), 527–534. https://doi.org/10.1370/afm.1518  

  11. Fieke Linskens, F. G., van der Scheer, E. S., Stortenbeker, I., Das, E., Staal, J. B., & van Lankveld, W. (2023). Negative language use of the physiotherapist in low back pain education impacts anxiety and illness beliefs: A randomised controlled trial in healthy respondents. Patient education and counseling, 110, 107649. https://doi.org/10.1016/j.pec.2023.107649  

  12. Martinez-Calderon, J., Struyf, F., Meeus, M., & Luque-Suarez, A. (2018). The association between pain beliefs and pain intensity and/or disability in people with shoulder pain: A systematic review. Musculoskeletal science & practice, 37, 29–57. https://doi.org/10.1016/j.msksp.2018.06.010  

  13. Stovner, L. J., Oftedal, G., Straume, A., & Johnsson, A. (2008). Nocebo as headache trigger: evidence from a sham-controlled provocation study with RF fields. Acta neurologica Scandinavica. Supplementum, 188, 67–71. https://doi.org/10.1111/j.1600-0404.2008.01035.x  

  14. Luparello, T., Lyons, H. A., Bleecker, E. R., & McFadden, E. R., Jr (1968). Influences of suggestion on airway reactivity in asthmatic subjects. Psychosomatic medicine, 30(6), 819–825. https://doi.org/10.1097/00006842-196811000-00002  

  15. Sweeney, O. J., Parepalli, S. A., Mirtorabi, N., Loo Yong Kee, K., Feakins, B. G., Aronson, J. K., & Wartolowska, K. A. (2022). Placebo's invisible brother: a restricted scoping review of the biomedical literature on the nocebo effect. Pain, 163(11), 2103–2111. https://doi.org/10.1097/j.pain.0000000000002629  

  16. Baker, D. B., Greenland, S., Mendlein, J., & Harmon, P. (1988). A health study of two communities near the Stringfellow Waste Disposal site. Archives of environmental health, 43(5), 325–334. https://doi.org/10.1080/00039896.1988.9934943  

  17. Bingel U. (2020). Placebo 2.0: the impact of expectations on analgesic treatment outcome. Pain, 161 Suppl 1, S48–S56. https://doi.org/10.1097/j.pain.0000000000001981  

  18. Blasini, M., Corsi, N., Klinger, R., & Colloca, L. (2017). Nocebo and pain: An overview of the psychoneurobiological mechanisms. Pain reports, 2(2), e585. https://doi.org/10.1097/PR9.0000000000000585  

  19. Zou, K., Wong, J., Abdullah, N., Chen, X., Smith, T., Doherty, M., & Zhang, W. (2016). Examination of overall treatment effect and the proportion attributable to contextual effect in osteoarthritis: meta-analysis of randomised controlled trials. Annals of the rheumatic diseases, 75(11), 1964–1970. https://doi.org/10.1136/annrheumdis-2015-208387 

  20. Häuser, W., Bartram-Wunn, E., Bartram, C., Reinecke, H., & Tölle, T. (2011). Systematic review: Placebo response in drug trials of fibromyalgia syndrome and painful peripheral diabetic neuropathy-magnitude and patient-related predictors. Pain, 152(8), 1709–1717. https://doi.org/10.1016/j.pain.2011.01.050  

  21. Menke J. M. (2014). Do manual therapies help low back pain? A comparative effectiveness meta-analysis. Spine, 39(7), E463–E472. https://doi.org/10.1097/BRS.0000000000000230  

  22. Hartvigsen, J., Kamper, S. J., & French, S. D. (2022). Low-value care in musculoskeletal health care: Is there a way forward?. Pain practice : the official journal of World Institute of Pain, 22 Suppl 2(Suppl 2), 65–70. https://doi.org/10.1111/papr.13142  

  23. O'Keeffe, M., Traeger, A. C., Michaleff, Z. A., Décary, S., Garcia, A. N., & Zadro, J. R. (2020). Overcoming Overuse Part 3: Mapping the Drivers of Overuse in Musculoskeletal Health Care. The Journal of orthopaedic and sports physical therapy, 50(12), 657–660. https://doi.org/10.2519/jospt.2020.0111  

  24. Saini, V., Garcia-Armesto, S., Klemperer, D., Paris, V., Elshaug, A. G., Brownlee, S., Ioannidis, J. P. A., & Fisher, E. S. (2017). Drivers of poor medical care. Lancet (London, England), 390(10090), 178–190. https://doi.org/10.1016/S0140-6736(16)30947-3  

  25. Abhishek, A., & Doherty, M. (2013). Mechanisms of the placebo response in pain in osteoarthritis. Osteoarthritis and cartilage, 21(9), 1229–1235. https://doi.org/10.1016/j.joca.2013.04.018  

  26. Doherty, M., & Dieppe, P. (2009). The "placebo" response in osteoarthritis and its implications for clinical practice. Osteoarthritis and cartilage, 17(10), 1255–1262. https://doi.org/10.1016/j.joca.2009.03.023  

  27. Ezzatvar, Y., Dueñas, L., Balasch-Bernat, M., Lluch-Girbés, E., & Rossettini, G. (2024). Which portion of physiotherapy treatments' effect is attributable to contextual effects in people with musculoskeletal pain?: A meta-analysis of randomised placebo-controlled trials. The Journal of orthopaedic and sports physical therapy, 1–28. Advance online publication. https://doi.org/10.2519/jospt.2024.12126




This blog was written by Samuel Bulten


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