Abstract
Background: Increasing evidence for the efficacy of analgesic placebo effects in laboratory studies with healthy persons raises the question whether placebos could be used to improve the treatment of pain patients. Expectancies play a central role in shaping analgesic placebo but also nocebo effects. Objectives: We investigated to what extent a sham opioid infusion (saline solution) produces sustained clinically relevant placebo and nocebo effects in chronic back pain patients. Methods: Fifty-nine patients received the sham opioid infusion applied via a large drain dressing and were compared to 14 control patients without intervention (natural history, NH) while experimental pain stimuli were applied. All subjects were told that the infusion would decrease pain although in rare cases pain increase would be possible (induction of expectancy). In addition, conditioning was introduced where the participants either experienced a decrease in experimental pain (n = 17; placebo conditioning), an increase (n = 21; nocebo conditioning), or no change (n = 21, no conditioning). Results: Compared to the NH group, all infusion groups showed positive treatment expectancies and significantly (p < 0.001) reduced clinical back pain (primary outcome) and pain-related disability (secondary outcome, assessed by self-reported functional capacity and perceived impairment of mobility). Even the nocebo conditioned group experiencing increased experimental pain developed positive treatment expectancies followed by reduced pain experience. Positive treatment expectancies and relief in clinical back pain were significantly positively correlated (r = 0.72, p < 0.01). Conclusions: These findings suggest that it may be beneficial to explicitly shape and integrate treatment expectancies into clinical pain management.
References
1.
Linde
K
, Clausius
N
, Ramirez
G
, Melchart
D
, Eitel
F
, Hedges
LV
, et al. Are the clinical effects of homeopathy placebo effects? A meta-analysis of placebo-controlled trials
. Lancet
. 1997
Sep
;350
(9081
):834
–43
.
[PubMed]
0140-67362.
Vase
L
, Riley
JL
3rd, Price
DD
. A comparison of placebo effects in clinical analgesic trials versus studies of placebo analgesia
. Pain
. 2002
Oct
;99
(3
):443
–52
.
[PubMed]
0304-39593.
Price
DD
, Finniss
DG
, Benedetti
F
. A comprehensive review of the placebo effect: recent advances and current thought
. Annu Rev Psychol
. 2008
;59
(1
):565
–90
.
[PubMed]
0066-43084.
Petrovic
P
. Placebo analgesia and nocebo hyperalgesia—two sides of the same coin?
Pain
. 2008
May
;136
(1-2
):5
–6
.
[PubMed]
0304-39595.
Mondaini
N
, Gontero
P
, Giubilei
G
, Lombardi
G
, Cai
T
, Gavazzi
A
, et al. Finasteride 5 mg and sexual side effects: how many of these are related to a nocebo phenomenon?
J Sex Med
. 2007
Nov
;4
(6
):1708
–12
.
[PubMed]
1743-60956.
Barsky
AJ
, Saintfort
R
, Rogers
MP
, Borus
JF
. Nonspecific medication side effects and the nocebo phenomenon
. JAMA
. 2002
Feb
;287
(5
):622
–7
.
[PubMed]
0098-74847.
Colloca
L
, Sigaudo
M
, Benedetti
F
. The role of learning in nocebo and placebo effects
. Pain
. 2008
May
;136
(1-2
):211
–8
.
[PubMed]
0304-39598.
Kaptchuk
TJ
, Miller
FG
. Placebo effects in medicine
. N Engl J Med
. 2015
Jul
;373
(1
):8
–9
.
[PubMed]
0028-47939.
Evers
AW
, Colloca
L
, Blease
C
, Annoni
M
, Atlas
LY
, Benedetti
F
, et al. Implications of Placebo and Nocebo Effects for Clinical Practice: expert Consensus
. Psychother Psychosom
. 2018
;87
(4
):204
–10
.
[PubMed]
0033-319010.
Klinger
R
, Kothe
R
, Schmitz
J
, Kamping
S
, Flor
H
. Placebo effects of a sham opioid solution: a randomized controlled study in patients with chronic low back pain
. Pain
. 2017
Oct
;158
(10
):1893
–902
.
[PubMed]
0304-395911.
Müller
M
, Kamping
S
, Benrath
J
, Skowronek
H
, Schmitz
J
, Klinger
R
, et al. Treatment history and placebo responses to experimental and clinical pain in chronic pain patients
. Eur J Pain
. 2016
Oct
;20
(9
):1530
–41
.
[PubMed]
1090-380112.
Colloca
L
, Tinazzi
M
, Recchia
S
, Le Pera
D
, Fiaschi
A
, Benedetti
F
, et al. Learning potentiates neurophysiological and behavioral placebo analgesic responses
. Pain
. 2008
Oct
;139
(2
):306
–14
.
[PubMed]
0304-395913.
Finniss
DG
, Benedetti
F
. Mechanisms of the placebo response and their impact on clinical trials and clinical practice
. Pain
. 2005
Mar
;114
(1-2
):3
–6
.
[PubMed]
0304-395914.
Enck
P
, Bingel
U
, Schedlowski
M
, Rief
W
. The placebo response in medicine: minimize, maximize or personalize?
Nat Rev Drug Discov
. 2013
Mar
;12
(3
):191
–204
.
[PubMed]
1474-177615.
Enck
P
, Benedetti
F
, Schedlowski
M
. New insights into the placebo and nocebo responses
. Neuron
. 2008
Jul
;59
(2
):195
–206
.
[PubMed]
0896-627316.
Bąbel
P
, Bajcar
EA
, Adamczyk
W
, Kicman
P
, Lisińska
N
, Świder
K
, et al. Classical conditioning without verbal suggestions elicits placebo analgesia and nocebo hyperalgesia
. PLoS One
. 2017
Jul
;12
(7
):e0181856
.
[PubMed]
1932-620317.
Colloca
L
, Benedetti
F
. How prior experience shapes placebo analgesia
. Pain
. 2006
Sep
;124
(1-2
):126
–33
.
[PubMed]
0304-395918.
Colloca
L
, Benedetti
F
. Placebo analgesia induced by social observational learning
. Pain
. 2009
Jul
;144
(1-2
):28
–34
.
[PubMed]
0304-395919.
Colloca
L
, Petrovic
P
, Wager
TD
, Ingvar
M
, Benedetti
F
. How the number of learning trials affects placebo and nocebo responses
. Pain
. 2010
Nov
;151
(2
):430
–9
.
[PubMed]
0304-395920.
Klinger
R
, Flor
H
. Clinical and ethical implications of placebo effects: enhancing patients’ benefits from pain treatment
. Handb Exp Pharmacol
. 2014
;225
:217
–35
.
[PubMed]
0171-200421.
Fava
GA
, Guidi
J
, Rafanelli
C
, Rickels
K
. The clinical inadequacy of the placebo model and the development of an alternative conceptual framework
. Psychother Psychosom
. 2017
;86
(6
):332
–40
.
[PubMed]
0033-319022.
Faul
F
, Erdfelder
E
, Lang
AG
, Buchner
A
. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences
. Behav Res Methods
. 2007
May
;39
(2
):175
–91
.
[PubMed]
1554-351X23.
Koes
BW
, van Tulder
M
, Lin
CW
, Macedo
LG
, McAuley
J
, Maher
C
. An updated overview of clinical guidelines for the management of non-specific low back pain in primary care
. Eur Spine J
. 2010
Dec
;19
(12
):2075
–94
.
[PubMed]
0940-671924.
Hautzinger
M
, Bailer
M
. Allgemeine Depressions Skala (ADS). Deutsche Form der “Center for Epidemiologic Studies Depression Scale (CES-D)
[General Depression Scale (ADS). German version of the Center for Epidemiologigic Studies Depression Scale
]Göttingen
: Beltz Test GmbH
; 1993
.25.
Laux
L
, Spielberger
CD
. Das State-Trait-Angstinventar: STAI
[The State-Trait Anxiety Inventory: STAI
]Göttingen
: Beltz Test
; 2001
.26.
Kam-Hansen
S
, Jakubowski
M
, Kelley
JM
, Kirsch
I
, Hoaglin
DC
, Kaptchuk
TJ
, et al. Altered placebo and drug labeling changes the outcome of episodic migraine attacks
. Sci Transl Med
. 2014
Jan
;6
(218
):218ra5
.
[PubMed]
1946-623427.
Bromm
B
, Meier
W
. The intracutaneous stimulus: a new pain model for algesimetric studies
. Methods Find Exp Clin Pharmacol
. 1984
Jul
;6
(7
):405
–10
.
[PubMed]
0379-035528.
P. B
. Pain and the brain: from nociception to cognition
. New York
: Raven Press
; 1995
.29.
Pollo
A
, Vighetti
S
, Rainero
I
, Benedetti
F
. Placebo analgesia and the heart
. Pain
. 2003
Mar
;102
(1-2
):125
–33
.
[PubMed]
0304-395930.
Voudouris
NJ
, Peck
CL
, Coleman
G
. The role of conditioning and verbal expectancy in the placebo response
. Pain
. 1990
Oct
;43
(1
):121
–8
.
[PubMed]
0304-395931.
Kohlmann
T
, Raspe
H
. Der Funktionsfragebogen Hannover zur alltagsnahen Diagnostik der Funktionsbeeinträchtigung durch Rückenschmerzen (FFbH-R)
. [Hannover functional questionnaire in ambulatory diagnosis of functional disability caused by back-ache]
. Rehabilitation (Stuttg)
. 1996
Feb
;35
(1
):I
–VIII
.
[PubMed]
0034-353632.
Roese
I
, Kohlmann
T
, Raspe
H
. [Measuring functional capacity in backache patients in rehabilitation: a comparison of standardized questionnaires]
. Rehabilitation (Stuttg)
. 1996
May
;35
(2
):103
–8
.
[PubMed]
0034-353633.
Roland
M
, Morris
R
. A study of the natural history of back pain. Part I: development of a reliable and sensitive measure of disability in low-back pain
. Spine
. 1983
Mar
;8
(2
):141
–4
.
[PubMed]
0362-243634.
Voudouris
NJ
, Peck
CL
, Coleman
G
. Conditioned placebo responses
. J Pers Soc Psychol
. 1985
Jan
;48
(1
):47
–53
.
[PubMed]
0022-351435.
Voudouris
NJ
, Peck
CL
, Coleman
G
. Conditioned response models of placebo phenomena: further support
. Pain
. 1989
Jul
;38
(1
):109
–16
.
[PubMed]
0304-395936.
Montgomery
GH
, Kirsch
I
. Classical conditioning and the placebo effect
. Pain
. 1997
Aug
;72
(1-2
):107
–13
.
[PubMed]
0304-395937.
Deyo
RA
, Von Korff
M
, Duhrkoop
D
. Opioids for low back pain
. BMJ
. 2015
Jan
;350
jan05 10
:g6380
.
[PubMed]
0959-813838.
Blasini
M
, Corsi
N
, Klinger
R
, Colloca
L
. Nocebo and pain: an overview of the psychoneurobiological mechanisms
. Pain Rep
. 2017
Mar-Apr
;2
(2
):e585
.
[PubMed]
2471-253139.
Klosterhalfen
S
, Kellermann
S
, Braun
S
, Kowalski
A
, Schrauth
M
, Zipfel
S
, et al. Gender and the nocebo response following conditioning and expectancy
. J Psychosom Res
. 2009
Apr
;66
(4
):323
–8
.
[PubMed]
0022-399940.
Bartels
DJ
, van Laarhoven
AI
, Haverkamp
EA
, Wilder-Smith
OH
, Donders
AR
, van Middendorp
H
, et al. Role of conditioning and verbal suggestion in placebo and nocebo effects on itch
. PLoS One
. 2014
Mar
;9
(3
):e91727
.
[PubMed]
1932-620341.
Peerdeman
KJ
, van Laarhoven
A
. I., Keij, S. M., Vase, L., Rovers, M. M., Peters, M. L., & Evers, A. W.: Relieving patients’ pain with expectation interventions: A meta-analysis
. J Pain
. 2016
;157
:1179
–91
. 1526-590042.
Colloca
L
, Finniss
D
. Nocebo effects, patient-clinician communication, and therapeutic outcomes
. JAMA
. 2012
Feb
;307
(6
):567
–8
.
[PubMed]
0098-748443.
Colloca
L
, Klinger
R
, Flor
H
, Bingel
U
. Placebo analgesia: psychological and neurobiological mechanisms
. Pain
. 2013
Apr
;154
(4
):511
–4
.
[PubMed]
0304-395944.
Tekampe
J
, van Middendorp
H
, Meeuwis
SH
, van Leusden
JW
, Pacheco-López
G
, Hermus
AR
, et al. Conditioning immune and endocrine parameters in humans: A systematic review
. Psychother Psychosom
. 2017
;86
(2
):99
–107
.
[PubMed]
0033-319045.
Levari
DE
, Gilbert
DT
, Wilson
TD
, Sievers
B
, Amodio
DM
, Wheatley
T
. Prevalence-induced concept change in human judgment
. Science
. 2018
Jun
;360
(6396
):1465
–7
.
[PubMed]
0036-807546.
47.
Zanna
MP
, Cooper
J
. Dissonance and the pill: an attribution approach to studying the arousal properties of dissonance
. J Pers Soc Psychol
. 1974
May
;29
(5
):703
–9
.
[PubMed]
0022-351448.
Totman
R
. Cognitive dissonance in the placebo treatment of insomnia— a pilot experiment
. Br J Med Psychol
. 1976
Dec
;49
(4
):393
–400
.
[PubMed]
0007-112949.
50.
Cormier
S
, Lavigne
GL
, Choinière
M
, Rainville
P
. Expectations predict chronic pain treatment outcomes
. Pain
. 2016
Feb
;157
(2
):329
–38
.
[PubMed]
0304-395951.
Haanstra
TM
, Kamper
SJ
, Williams
CM
, Spriensma
AS
, Lin
CW
, Maher
CG
, et al. Does adherence to treatment mediate the relationship between patients’ treatment outcome expectancies and the outcomes of pain intensity and recovery from acute low back pain?
Pain
. 2015
Aug
;156
(8
):1530
–6
.
[PubMed]
0304-395952.
Mondloch
MV
, Cole
DC
, Frank
JW
. Does how you do depend on how you think you’ll do? A systematic review of the evidence for a relation between patients’ recovery expectations and health outcomes
. CMAJ
. 2001
Jul
;165
(2
):174
–9
.
[PubMed]
0820-394653.
Sohl
SJ
, Schnur
JB
, Montgomery
GH
. A meta-analysis of the relationship between response expectancies and cancer treatment-related side effects
. J Pain Symptom Manage
. 2009
Nov
;38
(5
):775
–84
.
[PubMed]
0885-392454.
Carvalho
C
, Caetano
JM
, Cunha
L
, Rebouta
P
, Kaptchuk
TJ
, Kirsch
I
. Open-label placebo treatment in chronic low back pain: a randomized controlled trial
. Pain
. 2016
Dec
;157
(12
):2766
–72
.
[PubMed]
0304-395955.
Matsuoka
H
, Yoshiuchi
K
, Koyama
A
, Makimura
C
, Fujita
Y
, Tsurutani
J
, et al. Expectation of a Decrease in Pain Affects the Prognosis of Pain in Cancer Patients: a Prospective Cohort Study of Response to Morphine
. Int J Behav Med
. 2017
Aug
;24
(4
):535
–41
.
[PubMed]
1070-550356.
Kirsch
I
, Lynn
SJ
, Vigorito
M
, Miller
RR
. The role of cognition in classical and operant conditioning
. J Clin Psychol
. 2004
Apr
;60
(4
):369
–92
.
[PubMed]
0021-976257.
Kessner
S
, Wiech
K
, Forkmann
K
, Ploner
M
, Bingel
U
. The effect of treatment history on therapeutic outcome: an experimental approach
. JAMA Intern Med
. 2013
Aug
;173
(15
):1468
–9
.
[PubMed]
2168-610658.
Colloca
L
, Benedetti
F
. Placebos and painkillers: is mind as real as matter?
Nat Rev Neurosci
. 2005
Jul
;6
(7
):545
–52
.
[PubMed]
1471-003X59.
Klinger
R
, Flor
H
. Clinical and Ethical Implications of Placebo Effects: Enhancing Patients’ Benefits from Pain Treatment. In: Benedetti
F
, Enck
P
, Frisaldi
E
, Schedlowski
M
, editors. Placebo
. Berlin, Heidelberg
: Springer Berlin Heidelberg
; 2014
. pp. 217
–35
. 60.
Colloca
L
, Enck
P
, DeGrazia
D
. Relieving pain using dose-extending placebos: a scoping review
. Pain
. 2016
Aug
;157
(8
):1590
–8
.
[PubMed]
0304-395961.
Finniss
DG
, Kaptchuk
TJ
, Miller
F
, Benedetti
F
. Biological, clinical, and ethical advances of placebo effects
. Lancet
. 2010
Feb
;375
(9715
):686
–95
.
[PubMed]
0140-673662.
Klinger
R
, Colloca
L
, Bingel
U
, Flor
H
. Placebo analgesia: clinical applications
. Pain
. 2014
Jun
;155
(6
):1055
–8
.
[PubMed]
0304-395963.
Garland
EL
, Howard
MO
, Zubieta
JK
, Froeliger
B
. Restructuring hedonic dysregulation in chronic pain and prescription opioid misuse: effects of mindfulness-oriented recovery enhancement on responsiveness to drug cues and natural rewards
. Psychother Psychosom
. 2017
;86
(2
):111
–2
.
[PubMed]
0033-3190© 2019 S. Karger AG, Basel
2019
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