Manchikanti et al • Placebo and Nocebo Effects of Sedation 349
Pain Physician Vol. 8, No. 4, 2005
Pain Physician. 2005;8:349-355, ISSN 1533-3159
A Randomized Trial
The Role of Placebo and Nocebo Effects of Perioperative
Administration of Sedatives and Opioids in
Interventional Pain Management
Laxmaiah Manchikanti, MD, Vidyasagar Pampati, MSc, and Kim Damron, RN
Among patients receiving interven-
tions for pain, the role of nonspecific
treatment effects on their outcomes has
been the subject of much interest and
controversy. Placebo and nocebo effects
are widely seen in medicine and biology;
however, their underlying psychological
and neurobiological mechanisms are only
beginning to be more fully understood.
a non-analgesic substance (or action)
Background: The role of nonspecifi c
treatment effects in the outcomes of patients
receiving interventions for pain has been the
subject of controversy and interest. While
the administration of placebo and its effects
have been widely studied, the role of placebo
and nocebo effects of active agents adminis-
tered prior to or during interventional tech-
niques has not been explored.
Objectives: The evaluation of placebo
and nocebo effects of sodium chloride solu-
tion and active agents (midazolam and fen-
tanyl) administered during interventional
Study Design: Randomized, placebo-
Methods : A total of 360 patients were
divided into three groups, with Group I re-
ceiving placebo, Group II receiving midazol-
am, and Group III receiving fentanyl.
At 3 months, information was obtained
with regards to their impressions or the ex-
perience of the study, compared to their pre-
vious experiences with the treatment and
sedation. They were asked to rate their ex-
perience as better, worse, or no change com-
pared to their previous experience.
Results: Between 13% to 30% of pa-
tients across all three groups of the study,
rated their pain relief following injection
as better than their previous experience. A
smaller proportion, 3% to 8%, of patients
in all three groups rated their experience fol-
lowing injection as worse than their previous
experience. The majority of patients, 67% to
79%, regardless of group, described no sig-
nifi cant differences as compared to their pre-
vious experiences with sedation and treat-
ment for cervical or lumbar facet joint pain.
Conclusion : In patients undergoing in-
terventional procedures, sodium chloride so-
lution, midazolam, and fentanyl produced
placebo effects in 13% to 15%, 15% to 20%,
and 18% to 30% of the patients respective-
ly. Similarly, a nocebo effect was seen in 5%
to 8% of the patients in the sodium chloride
group, 8% of the patients in the midazolam
group, and 3% to 8% of the patients in the
fentanyl group. It is concluded that positive
and negative effects may be seen either with
placebo or active agents in 13% to 30% of
Keywords: Placebo, nocebo, random-
ized, double-blind, sedation, cervical facet
joint pain, lumbar facet joint pain, midazol-
am, fentanyl, sodium chloride.
From: Pain Management Center of Paducah,
Laxmaiah Manchikanti, M.D., 2831 Lone Oak Road
Paducah, KY 42003.
Funding: Facilities and funding were provided by
Ambulatory Surgery Center and Pain Management
Center of Paducah, Paducah, KY
Confl ict of Interest: None
Disclaimer: There was no external funding in
preparation of this manuscript.
Manuscript received on 4/12/2005
Revision submitted on 6/8/2005
Second revision submitted on 9/30/2005
Accepted for publication on 10/1/2005
evokes a reduction in pain sensation,
perception and/or cognitive response(s).
By contrast, nocebo hyperalgesia represents
a phenomenon opposite that of placebo
analgesia, characteristically considered to be
a worsening or consistent lack of change
of symptoms after the administration
of some agent known to be effective.
However, nocebo effects in interventional
pain management need to be carefully
hyperalgesia, tachyphylaxis, tolerance,
and/or progression of the underlying
organic pathology causing increased
pain and diminished sensitivity to
particular pharmacologic agents. Drug-
induced hyperalgesia may be due to
pharmacological mechanisms, such as
in opioid hyperalgesia and diminished
sensitivity to pharmacologic agents may
be due to the down-regulation of opioid
sites secondary to neuropathic central
Placebo analgesia has been shown
to be one of the most successful models
in the study of placebo effect (1-8). From
both neuropharmacological and neuro-
anatomical viewpoints, placebo effects
have been widely studied. It is believed
to be secondary to the release of endog-
enous opioids. However, the involvement
of ascending monoaminergic and non-
opioid peptidergic (e.g., oxytocin, vaso-
pressin) systems have been described in
placebo and non-specific analgesia. The
mechanisms leading to the release of en-
dogenous opioids are believed to involve
both conditioning and cognitive factors
(6,9-11). It has also been shown that if
humans or animals are exposed to a bi-
ologically active medication, the efficacy
of a subsequently administered placebo
that physically resembles the initial active
drug will be enhanced (4-6,12-15). This
observation suggests that classical condi-
tioning of contextual cues associated with
drug action can contribute to the place-
bo response. A commonly-observed phe-
Manchikanti et al • Placebo and Nocebo Effects of Sedation355
Pain Physician Vol. 8, No. 4, 2005
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