Are placebo and drug-specific effects additive? Questioning basic assumptions of double-blinded randomized clinical trials and presenting novel study designs

Drug Discovery Today

Volumn 22, Issue 4, 2017, Pages 729-735

  Kube, Tobias ^a   Rief, Winfried ^a  

^a PHILIPPS UNIVERSITY MARBURG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

DRUG; PLACEBO;

BRAIN FUNCTION; CLINICAL OUTCOME; DOUBLE BLIND PROCEDURE; DRUG EFFECT; HUMAN; MODEL; OUTCOME VARIABLE; PLACEBO EFFECT; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; STUDY DESIGN; CLINICAL TRIAL (TOPIC); METHODOLOGY; PROCEDURES;

CLINICAL TRIALS AS TOPIC; DOUBLE-BLIND METHOD; HUMANS; PHARMACEUTICAL PREPARATIONS; RANDOMIZED CONTROLLED TRIALS AS TOPIC; RESEARCH DESIGN;

EID: 85008224699     PISSN: 13596446     EISSN: 18785832     Source Type: Journal    
DOI: 10.1016/j.drudis.2016.11.022     Document Type: Review

References (60)

1. 1 Sackett, D.L., et al. Evidence based medicine: what it is and what it isn't – it's about integrating individual clinical expertise and the best external evidence. Br. Med. J. 312 (1996), 71–72.
2. 2 Beecher, H.K., The powerful placebo. JAMA 159 (1955), 1602–1606.
3. 3 Benedetti, F., Placebo Effects. 2014, Oxford University Press.
4. 4 Finniss, D.G., et al. Biological, clinical, and ethical advances of placebo effects. Lancet 375 (2010), 686–695.
5. 5 Finniss, D.G., Benedetti, F., Mechanisms of the placebo response and their impact on clinical trials and clinical practice. Pain 114 (2005), 3–6.
6. 6 Rief, W., et al. Mechanisms involved in placebo and nocebo responses and implications for drug trials. Clin. Pharmacol. Ther. 90 (2011), 722–726.
7. 7 Rutherford, B.R., Roose, S.P., A model of placebo response in antidepressant clinical trials. Am. J. Psychiatry 170 (2013), 723–733.
8. 8 Rutherford, B.R., et al. Patient expectancy as a mediator of placebo effects in antidepressant clinical trials. Am. J. Psychiatry, 2016 Published online September 9, 2016. http://dx.doi.org/10.1176/appi.ajp.2016.16020225.
9. 9 Shedden Mora, M., et al. Lessons learned from placebo groups in antidepressant trials. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 366 (2011), 1879–1888.
10. 10 Enck, P., et al. The placebo response in clinical trials: more questions than answers. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 366 (2011), 1889–1895.
11. 11 Enck, P., et al. The placebo response in medicine: minimize, maximize or personalize?. Nat. Rev. Drug Discov. 12 (2013), 191–204.
12. 12 Kirsch, I., Are drug and placebo effects in depression additive?. Biol. Psychiatry 47 (2000), 733–735.
13. 13 Rutherford, B.R., et al. Clinic visits in late-life depression trials: effects on signal detection and therapeutic outcome. Am. J. Geriatric Psychiatry 22 (2014), 1452–1461.
14. 14 Bridge, J.A., et al. Placebo response in randomized controlled trials of antidepressants for pediatric major depressive disorder. Am. J. Psychiatry 166 (2009), 42–49.
15. 15 van Die, M.D., et al. Are we drawing the right conclusions from randomised placebo-controlled trials? A post-hoc analysis of data from a randomised controlled trial. BMC Med. Res. Methodol., 9, 2009, 41.
16. 16 Finnerup, N.B., et al. The evidence for pharmacological treatment of neuropathic pain. Pain 150 (2010), 573–581.
17. 17 Finnerup, N.B., et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 14 (2015), 162–173.
18. 18 Eccles, R., Importance of placebo effect in cough clinical trials. Lung 188 (2010), S53–S61.
19. 19 Katz, J., et al. Clinical trial outcome in neuropathic pain – relationship to study characteristics. Neurology 70 (2008), 263–272.
20. 20 Benedetti, F., et al. Increasing uncertainty in CNS clinical trials: the role of placebo, nocebo, and Hawthorne effects. Lancet Neurol. 15 (2016), 736–747.
21. 21 Lund, K., et al. Randomised controlled trials may underestimate drug effects: balanced placebo trial design. PLoS ONE, 9, 2014, e84104.
22. 22 Hammami, M.M., et al. Interaction between drug and placebo effects: a cross-over balanced placebo design trial. Trials, 11, 2010, 110.
23. 23 Benedetti, F., et al. Hidden administration of drugs. Clin. Pharmacol. Ther. 90 (2011), 651–661.
24. 24 Benedetti, F., et al. Potentiation of placebo analgesia by proglumide. Lancet, 346, 1995 1231–1231.
25. 25 Colloca, L., et al. Overt versus covert treatment for pain, anxiety, and Parkinson's disease. Lancet Neurol. 3 (2004), 679–684.
26. 26 Colloca, L., Benedetti, F., Placebos and painkillers: is mind as real as matter?. Nat. Rev. Neurosci. 6 (2005), 545–552.
27. 27 Lund, K., et al. The magnitude of placebo analgesia effects depends on how they are conceptualized. J. Psychosomat. Res. 79 (2015), 663–668.
28. 28 Vase, L., et al. Nocebo vs. placebo: the challenges of trial design in analgesia research. Clin. Pharmacol. Ther. 97 (2015), 143–150.
29. 29 Fava, M., et al. A double-blind, placebo-controlled study of aripiprazole adjunctive to antidepressant therapy among depressed outpatients with inadequate response to prior antidepressant therapy (ADAPT-A Study). Psychother. Psychosomat. 81 (2012), 87–97.
30. 30 Kam-Hansen, S., et al. Altered placebo and drug labeling changes the outcome of episodic migraine attacks. Sci. Translat. Med., 6, 2014, 218ra5.
31. 31 Bjorkedal, E., Flaten, M.A., Interaction between expectancies and drug effects: an experimental investigation of placebo analgesia with caffeine as an active placebo. Psychopharmacology 215 (2011), 537–548.
32. 32 Rief, W., Glombiewski, J.A., The hidden effects of blinded, placebo-controlled randomized trials: an experimental investigation. Pain 153 (2012), 2473–2477.
33. 33 Bingel, U., et al. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci. Translat. Med., 3, 2011, 70ra14.
34. 34 Schenk, L.A., et al. Expectation requires treatment to boost pain relief: an fMRI study. Pain 155 (2014), 150–157.
35. 35 Atlas, L.Y., et al. Dissociable influences of opiates and expectations on pain. J. Neurosci. 32 (2012), 8053–8064.
36. 36 Kong, J., et al. Expectancy and treatment interactions: a dissociation between acupuncture analgesia and expectancy evoked placebo analgesia. Neuroimage 45 (2009), 940–949.
37. 37 Kong, J., et al. An fMRI study on the interaction and dissociation between expectation of pain relief and acupuncture treatment. Neuroimage 47 (2009), 1066–1076.
38. 38 Petrovic, P., et al. A prefrontal non-opioid mechanism in placebo analgesia. Pain 150 (2010), 59–65.
39. 39 Eippert, F., et al. Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron 63 (2009), 533–543.
40. 40 Kong, J., Benedetti, F., Placebo and nocebo effects: an introduction to psychological and biological mechanisms. Handb. Exp. Pharmacol. 225 (2014), 3–15.
41. 41 Scott, D.J., et al. Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch. Gen. Psychiatry 65 (2008), 220–231.
42. 42 Wager, T.D., et al. Placebo effects on human mu-opioid activity during pain. Proc. Natl. Acad. Sci. U. S. A. 104 (2007), 11056–11061.
43. 43 Zubieta, J.K., et al. Placebo effects mediated by endogenous opioid activity on mu-opioid receptors. J. Neurosci. 25 (2005), 7754–7762.
44. 44 Benedetti, F., et al. Nonopioid placebo analgesia is mediated by CB1 cannabinoid receptors. Nat. Med. 17 (2011), 1228–1230.
45. 45 Muthen, B., Brown, H.C., Estimating drug effects in the presence of placebo response: causal inference using growth mixture modeling. Stat. Med. 28 (2009), 3363–3385.
46. 46 Petrovic, P., et al. Placebo and opioid analgesia – imaging a shared neuronal network. Science 295 (2002), 1737–1740.
47. 47 Mitsikostas, D.D., et al. Nocebo is the enemy, not placebo. A meta-analysis of reported side effects after placebo treatment in headaches. Cephalalgia 31 (2011), 550–561.
48. 48 Mitsikostas, D.D., et al. Nocebo in fibromyalgia: meta-analysis of placebo-controlled clinical trials and implications for practice. Eur. J. Neurol. 19 (2012), 672–680.
49. 49 Papadopoulos, D., Mitsikostas, D.D., Nocebo effects in multiple sclerosis trials: a meta-analysis. Multiple Scler. J. 16 (2010), 816–828.
50. 50 Papadopoulos, D., Mitsikostas, D.D., A meta-analytic approach to estimating nocebo effects in neuropathic pain trials. J. Neurol. 259 (2012), 436–447.
51. 51 Rief, W., et al. Differences in adverse effect reporting in placebo groups in SSRI and tricyclic antidepressant trials a systematic review and meta-analysis. Drug Safety 32 (2009), 1041–1056.
52. 52 Amanzio, M., et al. A systematic review of adverse events in placebo groups of anti-migraine clinical trials. Pain 146 (2009), 261–269.
53. 53 Barron, A.J., et al. Systematic review of genuine versus spurious side-effects of beta-blockers in heart failure using placebo control: recommendations for patient information. Int. J. Cardiol. 168 (2013), 3572–3579.
54. 54 Moncrieff, J., A comparison of antidepressant trials using active and inert placebos. Int. J. Meth. Psychiatric Res. 12 (2003), 117–127.
55. 55 Wheeler, J.A., Zurek, W.H., Quantum Theory and Measurement. 2014, Princeton University Press.
56. 56 Wager, T.D., Roy, M., Separate mechanisms for placebo and opiate analgesia?. Pain 150 (2010), 8–9.
57. 57 Marlatt, G.A., Rohsenow, D.J., Cognitive processes in alcohol use: expectancy and the balanced placebo design. Adv. Substance Abuse Behav. Biol. Res. 1 (1980), 159–199.
58. 58 Miller, F.G., et al. Deception in research on the placebo effect. PLoS Med. 2 (2005), 853–859.
59. 59 Martin, A.L., Katz, J., Inclusion of authorized deception in the informed consent process does not affect the magnitude of the placebo effect for experimentally induced pain. Pain 149 (2010), 208–215.
60. 60 Rheker, J., et al. Learning to experience side effects after antidepressant intake: results from a randomized, controlled, double-blind study. Psychopharmacology, 2016 Published online November 2, 2016. http://dx.doi.org/10.1007/s00213-016-4466-8.