- Email: [email protected]
Understanding placebo effects in rheumatology
Joint Bone Spine 82 (2015) 222–224
Available online at
ScienceDirect www.sciencedirect.com
Editorial
Understanding placebo effects in rheumatology
a r t i c l e
i n f o
Keywords: Placebo effect Placebo response Osteoarthritis Chronic pain Nocebo
Placebo is any inert substance or a sham procedure that does not have an effect on the disease process per se, and is not expected to have any influence on its signs and symptoms. On the contrary, most patients who unknowingly receive a placebo instead of the active medicine in clinical trials report improvement in symptoms, and this is often clinically significant. This is called the placebo response [1], and can be defined as the symptomatic improvement on unknowingly receiving an inert and non-therapeutic intervention in the place of an active treatment. It can be measured as the within group difference in outcome for patients in the control arm of a placebo controlled randomized controlled trial (RCT) [2] (Fig. 1). Placebo effect is closely related to placebo response, and the two are often confused. In brief, placebo effect is that part of the placebo response which can be specifically attributed to the surreptitious receipt of placebo in the place of active medicine. It is measured as the difference in outcome between a control group and a notreatment group in a three arm RCT (Fig. 1), in a open-hidden or crossover study [2]. It excludes symptomatic improvement due to other factors like natural variations in disease severity, regression to the mean, spontaneous disease remission, and Hawthorne effect (behavior change while being observed) which may form part of the placebo response [3]. Thus, it can be inferred that placebo effect only results from the therapeutic ritual and the context in which treatment is delivered whereas placebo response results from the placebo effect and other factors mentioned above. Although placebo response and placebo effect have been used interchangeably, it is important to understand that they are different. Placebo response is of particular relevance to the clinician who aims to improve the patient’s symptoms, while placebo effect is more important for the researcher trying to understand its’ mechanisms. The psychological, neuro-chemical, and neuro-anatomic basis of placebo effect has been recognised in the last few decades and it is clear that it results from true biological effects and is not just a “trick of the mind”. Expectation from verbal and observational clues, conditioning, reward mechanisms, verbal suggestion mediated relief in anxiety, previous experience of effectiveness, and observed drug effectiveness in others are the main psychological mediators of
placebo responsiveness [4]. Additionally, endorsement of the intervention by public figures might also enhance the magnitude of the placebo response. Most research on the mechanism of placebo effect focuses on placebo analgesia, which mainly occurs due to the release of endogenous opioids. It has been shown experimentally that the administration of a placebo reduces the binding of the -opioid receptor selective radiotracer [11C] carfentalin to their receptors (suggesting placebo induced endogenous opiate release) [5]. Similarly, in some experimental models of pain, naloxone (an opiate antagonist) can block placebo response [6]. However, placebo analgesia is additive to opiate analgesia, and they act on different regions of the brain, with placebo analgesia having an earlier onset of action [7]. Thus, optimum pain relief can be obtained by pairing effective medications and expectation of pain relief [7]. Unlike placebo analgesia produced by expectation and conditioning with opiates, that produced by conditioning with non-steroidal antiinflammatory drugs (NSAIDs) is not antagonized by naloxone [6] raising the possibility of involvement of other neurotransmitters. One of these neurotransmitters may be dopamine. Both dopamine and opiates are released in response to placebos and their levels are reduced during nocebo states [8]. Nocebo effect (opposite of placebo effect) is a worsening in illness or onset of new symptoms due to expectation, or apprehension of an adverse effect when actually receiving an inert treatment. Another neurotransmitter, cholecystokinin produces nocebo response, whereas cholecystokinin antagonists like proglumide promote placebo effect [9]. Almost the entire pain processing pathway is involved in placebo analgesia. Parts of the frontal lobe are activated during the anticipatory phase of placebo response and in turn activate other regions of the brain [10,11]. Parts of the brain involved in short and long term memory, and semantics/linguistic areas are activated in verbal suggestion mediated placebo response [12]. Subsequently, the subcortical anti-nociceptive network, and descending pain modulatory pathways are activated [13,14]. Activity in the regions involved in pain transmission, like the thalamus, anterior insula, caudal RACC, and dorsal horn of spinal cord are diminished during placebo analgesia [13,15]. These neuro-anatomic and other neurochemical findings provide biological validity to the concept of placebo response. The neural mechanism of placebo response may be similar to that of hypnosis, with both placebo analgesia and hypnotic analgesia involving activation of similar regions of the cerebral cortex [16]. Of all symptoms pain is the most placebo responsive [17]. As pain is the most common symptom in rheumatic diseases, placebo response is of particular relevance to rheumatologists. Pain from
http://dx.doi.org/10.1016/j.jbspin.2015.01.013 1297-319X/© 2015 Published by Elsevier Masson SAS on behalf of the Société Française de Rhumatologie.
Editorial / Joint Bone Spine 82 (2015) 222–224
Mean symptom score
15 12
9 Start Finish
6 3 0 Acve
Placebo
No treatment
Arms of a randomised controlled trial Fig. 1. Placebo response and placebo effect. Placebo response (black vertical line with arrowheads) is the improvement in symptoms by the end of a trial in those treated surreptitiously with placebo alone. Placebo effect (red vertical line with arrowheads) is the difference in improvement in those treated with placebo and those who have had no treatment by the end of the trial.
osteoarthritis (OA) also shows excellent placebo responsiveness. In three OA trials where placebo and no-treatment arms were present, the effect size (ES) (95% confidence interval (CI)) of placebo analgesia was 0.77 (0.65–0.89), compared to −0.08 (−0.65–0.48) for untreated controls. It is interesting to note that for OA related pain the ES of placebo (standardised improvement in pain from baseline) is larger than the specific additional benefit (standardised improvement from baseline minus the improvement from placebo) achieved with most conventional pharmacological therapies like analgesics and NSAIDs (ES 0.2–0.3) [18] suggesting that placebo response should be optimised when managing patients with chronic painful conditions like OA. However, the predictors of placebo responsiveness are not well studied. In OA, other subjective outcomes like joint stiffness, selfreported function, and physician’s global assessment also show placebo responsiveness with ES of 0.43–0.66 [3]. However, placebo response was not observed in objective outcomes like quadriceps strength, knee swelling, range of movement, and joint space narrowing [3]. For semi-objective parameters like timed walking distance that requires patient co-operation and effective analgesia, placebo has a lower effect (ES (95%CI) (0.22 [0.08–0.35])) compared to pain relief [3]. Thus, it can be inferred that placebo response is observed on continuous subjective measures, and not on binary subjective, objective physical or laboratory measures of disease [17]. Sham physical therapies like sham-ultrasound [19], shamTENS and placebo pills [20,21] show placebo analgesia. Similarly, high levels of placebo analgesia also occurs in fibromyalgia [22]. Although systematic reviews suggest that placebos do not affect ‘hard endpoints’ like biochemical parameters, conditioning mediated placebo responses have immunosuppressive effects [23]. For example, in classic conditioning experiments with simultaneous administration of flavored syrup (conditioned stimulus) and immunosuppressants (unconditioned stimulus) like cyclophosphamide [24] or cyclosporine [25], subsequent administration of the conditioned stimulus alone produced an immunosuppressive effect e.g. reduced leukocyte count [24], and impaired T lymphocyte function [25]. Regardless of its mechanisms, it is important to remember that the overall benefit from any treatment is a sum of the specific treatment effects, and the placebo responses. Thus, a clinician who employs strategies to enhance placebo response will achieve better outcomes than someone who does not adopt this strategy. “Contextual response” is a term used to encompass the many additional factors (expectancy, environment, patient-practitioner interaction)
223
that influence how a patient responds to a treatment that they receive in clinical care (where a placebo should not knowingly be administered). However, in order to use placebo/contextual response to enhance patient outcome and satisfaction, we need to know its main predictors, which have been reviewed earlier, and are summarized below [4]. Contextual response is enhanced by a warm, attentive, confident, and optimistic consultation i.e. a positive consultation. The practitioner’s optimism about treatment, reassurance about prognosis, desire to follow-up, and confidence in treatment, including sub-conscious confidence further optimizes the contextual response. Additionally, the patient’s perception of the practitioner’s competence, knowledge of being treated, and expectation of improvement with treatment increases the placebo response. The patient’s personality also affects the placebo response. Optimistic patients and those who demonstrate situational anxiety are likely to show a higher contextual response. On the contrary, pessimistic or habitually anxious (trait anxiety) patients are less susceptible to positive contextual factors. Some inter-individual susceptibility to placebo analgesia can be explained by neuro-chemical changes like Catechol-O-methyl transferase gene polymorphisms. Finally, several treatment specific factors affect placebo response. Invasive and frequent interventions, reputable brand and higher cost of treatment, and greater number of tablets associate with placebo response. Colour of tablets may also influence outcome. For example, blue or green tablets result in greater sedative placebo response and pink, orange or red tablets have greater stimulant placebo response. It is possible that the lower cost, lack of branding, and different appearances may explain the patient reported lack of efficacy when switched from innovator to generic drugs. Therapies that involve a high level of frequent lengthy physical contact with the practitioner e.g. physiotherapy provide higher levels of contextual/placebo response. However, it is clearly unethical to change treatment solely to induce a greater contextual response in practice or to knowingly deceive a patient by giving a treatment that has no specific effect on their condition. While enhancing contextual response in clinical practice, we should also avoid inducing nocebo responses. We commonly manage people with chronic painful conditions like OA and low back pain for which there are no definitive strong treatments, as well as people with inflammatory and multisystem diseases like rheumatoid arthritis, where there are potent disease modifying anti-rheumatic drugs with potentially severe side effects. It is important to avoid inducing nocebo effects in people with either of these contrasting conditions. The consultation should include accurate information on the disease and its management, but be delivered in a positive, supportive manner that avoids nihilism and undue pessimism. Potentially severe but uncommon manifestations of some diseases and their treatments should be mentioned but not overemphasized, and again explained in the context of support and care. Placebo response is regarded as a nuisance in RCTs since its magnitude makes it difficult to demonstrate clear superiority of a treatment over placebo either in terms of mean group differences or in the proportion of patients who achieve clinically important improvements. However, this magnitude of contextual response should be recognized and optimised to improve patient-centered outcomes in clinical care. In conclusion, placebo response has a mild-moderate effect on symptoms, but usually no effect on the actual disease process. However, such improvements may be beneficial in the management of chronic conditions where most treatments have only a modest specific benefit [18]. This is especially true for conditions like OA where the ES of placebo response is larger than the specific effect attributable to oral analgesics and NSAIDs [18]. Thus, placebo and contextual response should be optimised in clinical practice as
224
Editorial / Joint Bone Spine 82 (2015) 222–224
it improves patient outcome without any risks–a unique situation. Further research is required to quantify placebo responsiveness in other rheumatic conditions, and to develop a model consultation that enhances contextual effects in patients with chronic painful conditions for which no definitive treatment exists. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Beecher HK. The powerful placebo. J Am Med Assoc 1955;159:1602–6. [2] Enck P, Klosterhalfen S, Zipfel S. Novel study designs to investigate the placebo response. BMC Med Res Methodol 2011;11:90. [3] Zhang W, Robertson J, Jones AC, et al. The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials. Ann Rheum Dis 2008;67:1716–23. [4] Abhishek A, Doherty M. Mechanisms of the placebo response in pain in osteoarthritis. Osteoarthritis Cartilage 2013;21:1229–35. [5] Zubieta JK, Bueller JA, Jackson LR, et al. Placebo effects mediated by endogenous opioid activity on mu-opioid receptors. J Neurosci 2005;25:7754–62. [6] Amanzio M, Benedetti F. Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. J Neurosci 1999;19:484–94. [7] Atlas LY, Whittington RA, Lindquist MA, et al. Dissociable influences of opiates and expectations on pain. J Neurosci 2012;32:8053–64. [8] Scott DJ, Stohler CS, Egnatuk CM, et al. Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch Gen Psychiatry 2008;65:220–31. [9] Benedetti F, Amanzio M, Casadio C, et al. Blockade of nocebo hyperalgesia by the cholecystokinin antagonist proglumide. Pain 1997;71:135–40. [10] Krummenacher P, Candia V, Folkers G, et al. Prefrontal cortex modulates placebo analgesia. Pain 2010;148:368–74. [11] Benedetti F, Arduino C, Costa S, et al. Loss of expectation-related mechanisms in Alzheimer’s disease makes analgesic therapies less effective. Pain 2006;121:133–44. [12] Craggs JG, Price DD, Robinson ME. Enhancing the placebo response: functional magnetic resonance imaging evidence of memory and semantic processing in placebo analgesia. J Pain 2014;15:435–46. [13] Eippert F, Finsterbusch J, Bingel U, et al. Direct evidence for spinal cord involvement in placebo analgesia. Science 2009;326:404. [14] Wager TD, Scott DJ, Zubieta JK. Placebo effects on human mu-opioid activity during pain. Proc Natl Acad Sci U S A 2007;104:11056–61. [15] Wager TD, Rilling JK, Smith EE, et al. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science 2004;303:1162–7. [16] Dillworth T, Mendoza ME, Jensen MP. Neurophysiology of pain and hypnosis for chronic pain. Transl Behav Med 2012;2:65–72. [17] Hrobjartsson A, Gotzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med 2001;344:1594–602.
[18] Osteoarthritis – National clinical guideline for care and management in adults. NICE and Royal College of Physicians guidelines on osteoarthritis. London: NICE; 2008. [19] Hashish I, Harvey W, Harris M. Anti-inflammatory effects of ultrasound therapy: evidence for a major placebo effect. Br J Rheumatol 1986;25:77–81. [20] Marchand S, Charest J, Li J, et al. Is TENS purely a placebo effect? A controlled study on chronic low back pain. Pain 1993;54:99–106. [21] Puhl AA, Reinhart CJ, Rok ER, et al. An examination of the observed placebo effect associated with the treatment of low back pain – a systematic review. Pain Res Manag 2011;16:45–52. [22] Hauser W, Bartram-Wunn E, Bartram C, et al. Systematic review: placebo response in drug trials of fibromyalgia syndrome and painful peripheral diabetic neuropathy-magnitude and patient-related predictors. Pain 2011;152:1709–17. [23] Meissner K, Distel H, Mitzdorf U. Evidence for placebo effects on physical but not on biochemical outcome parameters: a review of clinical trials. BMC Med 2007;5:3. [24] Giang DW, Goodman AD, Schiffer RB, et al. Conditioning of cyclophosphamideinduced leukopenia in humans. J Neuropsychiatry Clin Neurosci 1996;8:194–201. [25] Albring A, Wendt L, Benson S, et al. Preserving learned immunosuppressive placebo response: perspectives for clinical application. Clin Pharmacol Ther 2014;96:247–55.
Dr Abhishek Abhishek (PhD) a,b,∗,1 Prof Michael Doherty (MD) a a Arthritis Research UK Pain Centre, Academic Rheumatology, University of Nottingham, Nottingham, United Kingdom b Department of Rheumatology, Addenbrooke’s Hospital, Cambridge, United Kingdom ∗ Corresponding
author at: Academic Rheumatology, University of Nottingham, Nottingham NG5 1PB, United Kingdom. Tel.: +44115 823 1756; fax: +44115 823 1757. E-mail addresses: [email protected] (A. Abhishek), [email protected] (M. Doherty) 1 The corresponding author certifies that all authors approved the entirety of the submitted material and contributed actively to the study.
Accepted 19 January 2015 Available online 13 March 2015
Available online at
ScienceDirect www.sciencedirect.com
Editorial
Understanding placebo effects in rheumatology
a r t i c l e
i n f o
Keywords: Placebo effect Placebo response Osteoarthritis Chronic pain Nocebo
Placebo is any inert substance or a sham procedure that does not have an effect on the disease process per se, and is not expected to have any influence on its signs and symptoms. On the contrary, most patients who unknowingly receive a placebo instead of the active medicine in clinical trials report improvement in symptoms, and this is often clinically significant. This is called the placebo response [1], and can be defined as the symptomatic improvement on unknowingly receiving an inert and non-therapeutic intervention in the place of an active treatment. It can be measured as the within group difference in outcome for patients in the control arm of a placebo controlled randomized controlled trial (RCT) [2] (Fig. 1). Placebo effect is closely related to placebo response, and the two are often confused. In brief, placebo effect is that part of the placebo response which can be specifically attributed to the surreptitious receipt of placebo in the place of active medicine. It is measured as the difference in outcome between a control group and a notreatment group in a three arm RCT (Fig. 1), in a open-hidden or crossover study [2]. It excludes symptomatic improvement due to other factors like natural variations in disease severity, regression to the mean, spontaneous disease remission, and Hawthorne effect (behavior change while being observed) which may form part of the placebo response [3]. Thus, it can be inferred that placebo effect only results from the therapeutic ritual and the context in which treatment is delivered whereas placebo response results from the placebo effect and other factors mentioned above. Although placebo response and placebo effect have been used interchangeably, it is important to understand that they are different. Placebo response is of particular relevance to the clinician who aims to improve the patient’s symptoms, while placebo effect is more important for the researcher trying to understand its’ mechanisms. The psychological, neuro-chemical, and neuro-anatomic basis of placebo effect has been recognised in the last few decades and it is clear that it results from true biological effects and is not just a “trick of the mind”. Expectation from verbal and observational clues, conditioning, reward mechanisms, verbal suggestion mediated relief in anxiety, previous experience of effectiveness, and observed drug effectiveness in others are the main psychological mediators of
placebo responsiveness [4]. Additionally, endorsement of the intervention by public figures might also enhance the magnitude of the placebo response. Most research on the mechanism of placebo effect focuses on placebo analgesia, which mainly occurs due to the release of endogenous opioids. It has been shown experimentally that the administration of a placebo reduces the binding of the -opioid receptor selective radiotracer [11C] carfentalin to their receptors (suggesting placebo induced endogenous opiate release) [5]. Similarly, in some experimental models of pain, naloxone (an opiate antagonist) can block placebo response [6]. However, placebo analgesia is additive to opiate analgesia, and they act on different regions of the brain, with placebo analgesia having an earlier onset of action [7]. Thus, optimum pain relief can be obtained by pairing effective medications and expectation of pain relief [7]. Unlike placebo analgesia produced by expectation and conditioning with opiates, that produced by conditioning with non-steroidal antiinflammatory drugs (NSAIDs) is not antagonized by naloxone [6] raising the possibility of involvement of other neurotransmitters. One of these neurotransmitters may be dopamine. Both dopamine and opiates are released in response to placebos and their levels are reduced during nocebo states [8]. Nocebo effect (opposite of placebo effect) is a worsening in illness or onset of new symptoms due to expectation, or apprehension of an adverse effect when actually receiving an inert treatment. Another neurotransmitter, cholecystokinin produces nocebo response, whereas cholecystokinin antagonists like proglumide promote placebo effect [9]. Almost the entire pain processing pathway is involved in placebo analgesia. Parts of the frontal lobe are activated during the anticipatory phase of placebo response and in turn activate other regions of the brain [10,11]. Parts of the brain involved in short and long term memory, and semantics/linguistic areas are activated in verbal suggestion mediated placebo response [12]. Subsequently, the subcortical anti-nociceptive network, and descending pain modulatory pathways are activated [13,14]. Activity in the regions involved in pain transmission, like the thalamus, anterior insula, caudal RACC, and dorsal horn of spinal cord are diminished during placebo analgesia [13,15]. These neuro-anatomic and other neurochemical findings provide biological validity to the concept of placebo response. The neural mechanism of placebo response may be similar to that of hypnosis, with both placebo analgesia and hypnotic analgesia involving activation of similar regions of the cerebral cortex [16]. Of all symptoms pain is the most placebo responsive [17]. As pain is the most common symptom in rheumatic diseases, placebo response is of particular relevance to rheumatologists. Pain from
http://dx.doi.org/10.1016/j.jbspin.2015.01.013 1297-319X/© 2015 Published by Elsevier Masson SAS on behalf of the Société Française de Rhumatologie.
Editorial / Joint Bone Spine 82 (2015) 222–224
Mean symptom score
15 12
9 Start Finish
6 3 0 Acve
Placebo
No treatment
Arms of a randomised controlled trial Fig. 1. Placebo response and placebo effect. Placebo response (black vertical line with arrowheads) is the improvement in symptoms by the end of a trial in those treated surreptitiously with placebo alone. Placebo effect (red vertical line with arrowheads) is the difference in improvement in those treated with placebo and those who have had no treatment by the end of the trial.
osteoarthritis (OA) also shows excellent placebo responsiveness. In three OA trials where placebo and no-treatment arms were present, the effect size (ES) (95% confidence interval (CI)) of placebo analgesia was 0.77 (0.65–0.89), compared to −0.08 (−0.65–0.48) for untreated controls. It is interesting to note that for OA related pain the ES of placebo (standardised improvement in pain from baseline) is larger than the specific additional benefit (standardised improvement from baseline minus the improvement from placebo) achieved with most conventional pharmacological therapies like analgesics and NSAIDs (ES 0.2–0.3) [18] suggesting that placebo response should be optimised when managing patients with chronic painful conditions like OA. However, the predictors of placebo responsiveness are not well studied. In OA, other subjective outcomes like joint stiffness, selfreported function, and physician’s global assessment also show placebo responsiveness with ES of 0.43–0.66 [3]. However, placebo response was not observed in objective outcomes like quadriceps strength, knee swelling, range of movement, and joint space narrowing [3]. For semi-objective parameters like timed walking distance that requires patient co-operation and effective analgesia, placebo has a lower effect (ES (95%CI) (0.22 [0.08–0.35])) compared to pain relief [3]. Thus, it can be inferred that placebo response is observed on continuous subjective measures, and not on binary subjective, objective physical or laboratory measures of disease [17]. Sham physical therapies like sham-ultrasound [19], shamTENS and placebo pills [20,21] show placebo analgesia. Similarly, high levels of placebo analgesia also occurs in fibromyalgia [22]. Although systematic reviews suggest that placebos do not affect ‘hard endpoints’ like biochemical parameters, conditioning mediated placebo responses have immunosuppressive effects [23]. For example, in classic conditioning experiments with simultaneous administration of flavored syrup (conditioned stimulus) and immunosuppressants (unconditioned stimulus) like cyclophosphamide [24] or cyclosporine [25], subsequent administration of the conditioned stimulus alone produced an immunosuppressive effect e.g. reduced leukocyte count [24], and impaired T lymphocyte function [25]. Regardless of its mechanisms, it is important to remember that the overall benefit from any treatment is a sum of the specific treatment effects, and the placebo responses. Thus, a clinician who employs strategies to enhance placebo response will achieve better outcomes than someone who does not adopt this strategy. “Contextual response” is a term used to encompass the many additional factors (expectancy, environment, patient-practitioner interaction)
223
that influence how a patient responds to a treatment that they receive in clinical care (where a placebo should not knowingly be administered). However, in order to use placebo/contextual response to enhance patient outcome and satisfaction, we need to know its main predictors, which have been reviewed earlier, and are summarized below [4]. Contextual response is enhanced by a warm, attentive, confident, and optimistic consultation i.e. a positive consultation. The practitioner’s optimism about treatment, reassurance about prognosis, desire to follow-up, and confidence in treatment, including sub-conscious confidence further optimizes the contextual response. Additionally, the patient’s perception of the practitioner’s competence, knowledge of being treated, and expectation of improvement with treatment increases the placebo response. The patient’s personality also affects the placebo response. Optimistic patients and those who demonstrate situational anxiety are likely to show a higher contextual response. On the contrary, pessimistic or habitually anxious (trait anxiety) patients are less susceptible to positive contextual factors. Some inter-individual susceptibility to placebo analgesia can be explained by neuro-chemical changes like Catechol-O-methyl transferase gene polymorphisms. Finally, several treatment specific factors affect placebo response. Invasive and frequent interventions, reputable brand and higher cost of treatment, and greater number of tablets associate with placebo response. Colour of tablets may also influence outcome. For example, blue or green tablets result in greater sedative placebo response and pink, orange or red tablets have greater stimulant placebo response. It is possible that the lower cost, lack of branding, and different appearances may explain the patient reported lack of efficacy when switched from innovator to generic drugs. Therapies that involve a high level of frequent lengthy physical contact with the practitioner e.g. physiotherapy provide higher levels of contextual/placebo response. However, it is clearly unethical to change treatment solely to induce a greater contextual response in practice or to knowingly deceive a patient by giving a treatment that has no specific effect on their condition. While enhancing contextual response in clinical practice, we should also avoid inducing nocebo responses. We commonly manage people with chronic painful conditions like OA and low back pain for which there are no definitive strong treatments, as well as people with inflammatory and multisystem diseases like rheumatoid arthritis, where there are potent disease modifying anti-rheumatic drugs with potentially severe side effects. It is important to avoid inducing nocebo effects in people with either of these contrasting conditions. The consultation should include accurate information on the disease and its management, but be delivered in a positive, supportive manner that avoids nihilism and undue pessimism. Potentially severe but uncommon manifestations of some diseases and their treatments should be mentioned but not overemphasized, and again explained in the context of support and care. Placebo response is regarded as a nuisance in RCTs since its magnitude makes it difficult to demonstrate clear superiority of a treatment over placebo either in terms of mean group differences or in the proportion of patients who achieve clinically important improvements. However, this magnitude of contextual response should be recognized and optimised to improve patient-centered outcomes in clinical care. In conclusion, placebo response has a mild-moderate effect on symptoms, but usually no effect on the actual disease process. However, such improvements may be beneficial in the management of chronic conditions where most treatments have only a modest specific benefit [18]. This is especially true for conditions like OA where the ES of placebo response is larger than the specific effect attributable to oral analgesics and NSAIDs [18]. Thus, placebo and contextual response should be optimised in clinical practice as
224
Editorial / Joint Bone Spine 82 (2015) 222–224
it improves patient outcome without any risks–a unique situation. Further research is required to quantify placebo responsiveness in other rheumatic conditions, and to develop a model consultation that enhances contextual effects in patients with chronic painful conditions for which no definitive treatment exists. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Beecher HK. The powerful placebo. J Am Med Assoc 1955;159:1602–6. [2] Enck P, Klosterhalfen S, Zipfel S. Novel study designs to investigate the placebo response. BMC Med Res Methodol 2011;11:90. [3] Zhang W, Robertson J, Jones AC, et al. The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials. Ann Rheum Dis 2008;67:1716–23. [4] Abhishek A, Doherty M. Mechanisms of the placebo response in pain in osteoarthritis. Osteoarthritis Cartilage 2013;21:1229–35. [5] Zubieta JK, Bueller JA, Jackson LR, et al. Placebo effects mediated by endogenous opioid activity on mu-opioid receptors. J Neurosci 2005;25:7754–62. [6] Amanzio M, Benedetti F. Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. J Neurosci 1999;19:484–94. [7] Atlas LY, Whittington RA, Lindquist MA, et al. Dissociable influences of opiates and expectations on pain. J Neurosci 2012;32:8053–64. [8] Scott DJ, Stohler CS, Egnatuk CM, et al. Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch Gen Psychiatry 2008;65:220–31. [9] Benedetti F, Amanzio M, Casadio C, et al. Blockade of nocebo hyperalgesia by the cholecystokinin antagonist proglumide. Pain 1997;71:135–40. [10] Krummenacher P, Candia V, Folkers G, et al. Prefrontal cortex modulates placebo analgesia. Pain 2010;148:368–74. [11] Benedetti F, Arduino C, Costa S, et al. Loss of expectation-related mechanisms in Alzheimer’s disease makes analgesic therapies less effective. Pain 2006;121:133–44. [12] Craggs JG, Price DD, Robinson ME. Enhancing the placebo response: functional magnetic resonance imaging evidence of memory and semantic processing in placebo analgesia. J Pain 2014;15:435–46. [13] Eippert F, Finsterbusch J, Bingel U, et al. Direct evidence for spinal cord involvement in placebo analgesia. Science 2009;326:404. [14] Wager TD, Scott DJ, Zubieta JK. Placebo effects on human mu-opioid activity during pain. Proc Natl Acad Sci U S A 2007;104:11056–61. [15] Wager TD, Rilling JK, Smith EE, et al. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science 2004;303:1162–7. [16] Dillworth T, Mendoza ME, Jensen MP. Neurophysiology of pain and hypnosis for chronic pain. Transl Behav Med 2012;2:65–72. [17] Hrobjartsson A, Gotzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med 2001;344:1594–602.
[18] Osteoarthritis – National clinical guideline for care and management in adults. NICE and Royal College of Physicians guidelines on osteoarthritis. London: NICE; 2008. [19] Hashish I, Harvey W, Harris M. Anti-inflammatory effects of ultrasound therapy: evidence for a major placebo effect. Br J Rheumatol 1986;25:77–81. [20] Marchand S, Charest J, Li J, et al. Is TENS purely a placebo effect? A controlled study on chronic low back pain. Pain 1993;54:99–106. [21] Puhl AA, Reinhart CJ, Rok ER, et al. An examination of the observed placebo effect associated with the treatment of low back pain – a systematic review. Pain Res Manag 2011;16:45–52. [22] Hauser W, Bartram-Wunn E, Bartram C, et al. Systematic review: placebo response in drug trials of fibromyalgia syndrome and painful peripheral diabetic neuropathy-magnitude and patient-related predictors. Pain 2011;152:1709–17. [23] Meissner K, Distel H, Mitzdorf U. Evidence for placebo effects on physical but not on biochemical outcome parameters: a review of clinical trials. BMC Med 2007;5:3. [24] Giang DW, Goodman AD, Schiffer RB, et al. Conditioning of cyclophosphamideinduced leukopenia in humans. J Neuropsychiatry Clin Neurosci 1996;8:194–201. [25] Albring A, Wendt L, Benson S, et al. Preserving learned immunosuppressive placebo response: perspectives for clinical application. Clin Pharmacol Ther 2014;96:247–55.
Dr Abhishek Abhishek (PhD) a,b,∗,1 Prof Michael Doherty (MD) a a Arthritis Research UK Pain Centre, Academic Rheumatology, University of Nottingham, Nottingham, United Kingdom b Department of Rheumatology, Addenbrooke’s Hospital, Cambridge, United Kingdom ∗ Corresponding
author at: Academic Rheumatology, University of Nottingham, Nottingham NG5 1PB, United Kingdom. Tel.: +44115 823 1756; fax: +44115 823 1757. E-mail addresses: [email protected] (A. Abhishek), [email protected] (M. Doherty) 1 The corresponding author certifies that all authors approved the entirety of the submitted material and contributed actively to the study.
Accepted 19 January 2015 Available online 13 March 2015