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Placebo Effect and Pain - Part 1

May 2018

Understanding the placebo effect in clinical trials for painkillers

Psychological Therapy in Pain

May 2018

Pain is not all in a patient’s head, but can psychotherapy help?

Placebo Effect and Pain – Part 1

The placebo effect has become a focus in pain research. Here we consider how biological responses in the body and brain can occur in response to a placebo and how these responses can influence trial outcomes in pain. This article is part of a planned series focusing on clinical trials in pain, Placebo effect and pain – Part 2 will be published on PainSolve next month.

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Psychological Therapy in Pain

Pain is now recognised as a biopsychosocial phenomenon with far-ranging effects on biological, psychological and emotional processes. Here we explore different forms of psychological therapy that can be used as part of the multidisciplinary management of chronic pain.

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The placebo response: a hot topic for pain researchers?

The role of the placebo effect has become a focus in pain research due to its potential to reduce separation between the drug and control arms, and so influence the outcome in randomised controlled trials (RCTs).1 In clinical trials of analgesics, failure to demonstrate benefit over placebo has been a common finding over the past years.2 Many potentially effective analgesic compounds have been discarded in early drug development due to a lack of statistically significant reductions in pain reports in RCTs.2 For example, in the past 10 years it has been estimated that over 90% of candidate drugs in development for neuropathic and cancer pain have been discontinued after failing to show superiority compared with placebo.3

Placebo responses and symptom relief: from expectation to measurable biological effects

Although medical understanding of placebo responses is still far from complete, it is known that for certain conditions, especially those with subjective symptoms, patients receiving placebos may report similar health benefits to participants taking effective drugs.4 Placebos have measurable effects on many symptoms, including pain, depression, fatigue, and other perceptions of bodily dysfunction.4 Several interlinked neuropsychological and neurophysiologic mechanisms driving symptom improvements in response to placebo are recognised:5

  1. Priming and expectation: the patient believes that a particular intervention will provide benefit/relief. This expectation for the positive outcome seems to play a key role in placebo-related benefit, along with other factors such as optimism and social conditioning, and may produce a medium-sized benefit.
  2. Effects on brain activity: Functional imaging studies have confirmed that the placebo response of pain relief can be measured as neural activity documented in cortical areas directly associated with pain inhibition.
  3. Altered biochemical activity: Studies demonstrate that some placebo mechanisms operate by altering the activity of both cholecystokinin (CCK) and endogenous opioids. Other pain regulating pathways, for example involving dopamine and cannabinoid signalling, may also be involved in placebo responses.

The growing body of evidence demonstrating objective physiologic responses to placebo (in terms of measurable alterations in brain and biochemical activity) indicates that improvement in symptoms is a genuine effect, rather than simply spontaneous remission, normal symptom fluctuation, or regression to the mean.6

Are patients’ rising expectations for new pain medicines influencing trial outcomes?

A retrospective analysis of data from 84 published RCTs of drugs for the treatment of chronic neuropathic pain found that the placebo response (in terms of a reduction in pain) has grown over time: from an average of about 18% in the 1990s to an average of 30% by 2013.1 In contrast, the drug response remained stable, leading to a diminished treatment advantage. The authors attributed the increased placebo response to differences in the execution of trials within the US over this period – in particular, the growth in study size (from on average 50 patients per study in 1990, to over 700 per study in 2013), study duration (from on average 4 weeks per study in 1990 to 12 weeks in 2013) and the introduction of contract research organisations, whose clinical trialists may have provided more one-to-one support to patients than they would have received through routine care in primary/secondary care. These changes in trial format may enhance participants’ expectations of the treatment’s effectiveness.7 Similarly, exposure to direct-to-consumer advertising for medicines in the US may increase people’s expectations of the benefits of drugs, and has been proposed as a possible reason why the trend of a rising placebo response was observed in US neuropathic pain trials.3


  1. Tuttle AH, et al. Pain 2015; 156: 2616–26
  2. Frisaldi e, et al. Pain Ther 2017; 6: 107–110
  3. Marchant J. Nature 2015 News, Strong placebo response thwarts painkiller trials. Available at: https://www.nature.com/news/strong-placebo-response-thwarts-painkiller-trials-1.18511 (accessed 18 April 2018)
  4. Blease CR, et al. BMJ 2017; 356: j463
  5. Bhardwaj P, Yadav RK. Int J Clin Exp Physiology 2017; 4: 123–128
  6. Kaptchuk TJ, Miller FG. N Engl J Med 2015; 373: 8–9
  7. Scutti S. CNN 2016 Health, The real -- and growing -- effects of fake pills. Available at: https://edition.cnn.com/2016/10/27/health/placebo-effect-back-pain/index.html (accessed 18 April 2018)

The psychology of pain

Chronic pain is a highly intractable issue that is encountered by clinicians across hundreds of medical conditions.1 Pain can have multiple consequences for affected individuals, including increasing the likelihood for depression, inability to work, disruption to personal relationships, and suicidal thoughts.2 Chronic pain is also frequently accompanied by comorbid psychological disorders, together resulting in significant disability (as measured by impairment of daily activities).2 Since the 1960s, there has been progress in advancing understanding of pain, from seeing pain as a purely physical sensation to recognition that pain can often be a biopsychosocial phenomenon with far-ranging effects on biological, psychological and emotional processes.3,4 This view is reflected in the International Association for the Study of Pain (IASP) definition of pain as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’.5

Whilst the mechanisms behind the development of chronic pain are incompletely understood, one important contributor that has been identified is perceived stress and stress response systems.1 Supporting patients in better understanding their cognitive and emotional modulation of pain, and promoting self-management techniques through psychological treatments could be an overlooked, but key, part of the puzzle to solving pain.1

Psychological therapies as a tool to manage chronic pain

Psychological interventions are a recommended feature of a modern pain treatment service, where they can be effectively combined with medical treatment as part of the multidisciplinary management of chronic pain.6 Psychological therapies for pain are presumed to confer a low risk for adverse effects to the recipient.7 Rather than focusing on resolution of pain itself, psychotherapy for chronic pain primarily aims to improve physical, emotional, social, and occupational functioning.7

“There is no treatment for patients with chronic pain that makes a bigger difference than our empathy and our time.”1

Psychological therapies for chronic pain fall into four key categories (see table below):7

Therapeutic modality Description of treatment Pain disorders with demonstrated efficacy
Operant-behavioural therapy Treatment focuses on modifying behavioural responses though reinforcement and punishment contingencies, and extinction of associations between the threat value of pain and physical behaviour. Complex regional pain syndromes, lower back pain, mixed chronic pain, whiplash-associated disorders.
Cognitive-behavioural therapy (CBT) A biopsychosocial intervention focused on developing personal coping strategies. CBT protocols may involve psychoeducation about pain, behaviour, and mood, strategies for relaxation, effective communication, and cognitive restructuring for distorted and maladaptive thoughts about pain. Cancer, chronic lower back pain, chronic headaches, chronic migraines, chronic orofacial pain, complex regional pain syndromes, fibromyalgia, HIV/AIDS, Irritable bowel syndrome, mixed chronic pain, non-specific heart pain, multiple sclerosis, nonspecific musculoskeletal pain, osteoarthritis, rheumatoid arthritis, spinal cord injury, systemic lupus erythematosus, whiplash-associated disorders.
Mindfulness-based therapy A psychotherapy method that promotes a non-judgmental approach to pain and uncoupling of physical and psychological aspects of pain. Meditations and daily mindfulness practice are utilised to increase awareness of the body, breath and proprioceptive signals, and development of mindful activities. Arthritis, cancer, chronic lower back pain, chronic headache, chronic migraine, complex regional pain syndromes, fibromyalgia, irritable bowel syndrome, rheumatoid arthritis, chronic neck pain.
Acceptance and commitment therapy Treatment based on increasing psychological flexibility through acceptance of mental events and pain, and ceasing of maladaptive attempts to eliminate and control pain through avoidance and other problematic behaviours. Musculoskeletal pain (full body, lower back, lower limb, neck, upper limb), whiplash-associated disorders.

Beginning in the late 1970s and early 1980s, approaches to chronic pain based on CBT have become the dominant psychological approach within pain management.8,9 Among the various forms of psychotherapy applied for chronic pain, the evidence base for effectiveness is strongest for CBT.6 In adults, CBT has been evidenced to support marked improvements in quality of life, disability, psychological distress (principally depression) and, to a lesser extent, pain.6 The impact of CBT on pain is stronger in the paediatric population, where it has been described as ‘one of the most successful treatments for paediatric chronic pain’.6

Future directions to improve access to psychotherapy

Given the magnitude of the problem and the modest benefits from traditional medical, pharmacological, and surgical treatments, there is a growing realisation of the importance of considering psychosocial factors when addressing chronic pain and pain-related disability.4 An ideal pain management regimen will be comprehensive, integrative, and interdisciplinary, so including psychological interventions as part of a multimodal approach can provide a safe and effective means to help patients feel more in command of their pain control and enable them to live as normal a life as possible despite pain.10

Treatment accessibility may be a limitation for psychological intervention; for example, the availability of psychotherapists with appropriate expertise and experience in supporting patients with chronic pain management is limited in certain healthcare systems.7,9 Similarly, even when specialist support is available, patients in poverty or those living in remote geographical locations may struggle to access these.7 Technology allowing remote access, such as online video therapy sessions or virtual reality clinics, may help to improve access to these psychological therapies in pain management.7,11,12 Delivery of psychological interventions by healthcare professionals other than psychologists (for example nurses or physical therapists), or within collaborative care models in primary care (where a patient’s healthcare needs are supported in an integrated approach involving coordination with social and mental health teams) are gaining interest as innovative approaches to address access barriers.9


  1. Crofford LJ. Trans Am Clin Climatol Assoc 2015; 126: 167–183
  2. Goldberg DS, McGee SJ. BMC Public Health 2011; 11: 770
  3. Lumley MA, et al. J Clin Psychol 2011; 67: 942–968
  4. Jensen MP & Turk DC. Am Psychol 2014; 69: 105–118
  5. International Association for the Study of Pain (1994) IASP Taxonomy, Pain terms, Pain. Available at: https://www.iasp-pain.org/Taxonomy#Pain (accessed April 2018)
  6. Eccleston C, et al. Br J Anaesth 2013; 111: 59–63
  7. Sturgeon JA, et al. Psychol Res Behav Manag 2014; 7: 115–124
  8. Barker E & McCracken LM. Br J Pain 2014; 8: 98–106
  9. Ehde DM, et al. Am Psychol 2014; 69: 153–166
  10. Roditi D & Robinson ME. Psychol Res Behav Manag 2011; 4: 41–49
  11. Fisher E, et al. Cochrane Database Syst Rev. 2015; 3: CD011118
  12. Hoch DB, et al. PLoS ONE 7: e33843