Placebo treatments and healing rituals have been used to treat pain throughout history. The present within-subject crossover study examines the variability in individual responses to placebo treatment with verbal suggestion and visual cue conditioning by investigating whether responses to different types of placebo treatment, as well as conditioning responses, correlate with one another. Secondarily, this study also examines whether responses to sham acupuncture correlate with responses to genuine acupuncture. Healthy subjects were recruited to participate in two sequential experiments. Experiment one is a five-session crossover study. In each session, subjects received one of four treatments: placebo pills (described as Tylenol), sham acupuncture, genuine acupuncture, or no treatment rest control condition. Before and after each treatment, paired with a verbal suggestion of positive effect, each subject’s pain threshold, pain tolerance, and pain ratings to calibrated heat pain were measured. At least 14 days after completing experiment one, all subjects were invited to participate in experiment two, during which their analgesic responses to conditioned visual cues were tested. Forty-eight healthy subjects completed experiment one, and 45 completed experiment two. The results showed significantly different effects of genuine acupuncture, placebo pill and rest control on pain threshold. There was no significant association between placebo pills, sham acupuncture and cue conditioning effects, indicating that individuals may respond to unique healing rituals in different ways. This outcome suggests that placebo response may be a complex behavioral phenomenon that has properties that comprise a state, rather than a trait characteristic. This could explain the difficulty of detecting a signature for “placebo responders.” However, a significant association was found between the genuine and sham acupuncture treatments, implying that the non-specific effects of acupuncture may contribute to the analgesic effect observed in genuine acupuncture analgesia.
To perform a meta-analysis on the use of combined epidural-intrathecal analgesia during labor, including intrathecal fentanyl and/or morphine compared to usual epidural techniques.
The serotonin (5-hydroxtryptamine, 5-HT) system plays a role in analgesia and emesis. The aim of this study was to test whether opioids or ketamine inhibit the human 5-HT transporter and whether this increases free plasma 5-HT concentrations. HEK293 cells, stably transfected with the human 5-HT transporter cDNA, were incubated with morphine, hydromorphone, fentanyl, alfentanil, pethidine (meperidine), tramadol, ketamine, and the reference substance citalopram (specific 5-HT transporter inhibitor). The uptake of [(3)H]5-HT was measured by liquid scintillation counting. In a second series of experiments, study drugs were incubated with plasma of ten healthy blood donors and change of 5-HT plasma-concentrations were measured (ELISA). The end point was the inhibition of the 5-HT transporter by different analgesics either in HEK293 cells or in human platelets ex vivo. Tramadol, pethidine, and ketamine suppressed [(3)H]5-HT uptake dose-dependently with an IC50 of 1, 20.9, and 230 μM, respectively. These drugs also prevented 5-HT uptake in platelets with an increase in free plasma 5-HT. Free 5-HT concentrations in human plasma were increased by citalopram 1 μM, tramadol 20 μM, pethidine 30 μM, and ketamine 100 μM to 280 [248/312]%, 269 [188/349]%, and 149 [122/174]%, respectively, compared to controls without any co-incubation (means [95 % CI]; all p < 0.005). No change in both experimental settings was observed for the other opioids. Tramadol and pethidine inhibited the 5-HT transporter in HEK293 cells and platelets. This inhibition may contribute to serotonergic effects when these opioids are given in combination, e.g., with monoamine oxidase inhibitors or selective serotonin reuptake inhibitors.
Treatment for vaso-occlusive events (“crisis,” or VOC) in sickle cell disease (SCD) remains limited to symptom relief with opioids. Animal models support the effectiveness of the pan-selectin inhibitor GMI-1070 in reducing selectin-mediated cell adhesion and abrogating VOC. We studied GMI-1070 in a prospective multicenter, randomized, placebo-controlled, double-blind, Phase 2 study of 76 SCD patients with VOC. Study drug (GMI-1070 or placebo) was given q12h for up to 15 doses. Other treatment was per institutional standard of care. All subjects reached the composite primary endpoint of resolution of VOC. Although time to reach the composite primary endpoint was not statistically different between the groups, clinically meaningful reductions in mean and median times to VOC resolution of 41 and 63 hours (28% and 48%, P=.19 for both) were observed in the active treatment group versus placebo group. As a secondary endpoint, GMI-1070 appeared safe in acute vaso-occlusion, and adverse events were not different in the two arms. Also in secondary analyses, mean cumulative IV opioid analgesic use was reduced by 83% with GMI-1070 vs placebo (P=.010). These results support a Phase 3 study of GMI-1070 (now rivipansel) for SCD VOC. This study is registered to www.clinicaltrials.gov as NCT01119833.
Opioids may inhibit the serotonin and norepinephrine transporters (SERT and NET, respectively). NET inhibition may contribute to analgesia, and SERT inhibition or interactions with serotonin receptors may cause serotonergic toxicity. However, the effects of different opioids on the human SERT, NET, and serotonin receptors have not been sufficiently studied.
This review assessed how often neonates in control groups experienced unnecessary pain during clinical trials involving procedural pain. We retrieved 46 studies in the 30 months up to June 2015 and found that in 32 (70%) the control babies received either placebos or no treatment. Placebos were used in 16/25 (64%) studies involving heel pricks and in 6/7 (85%) involving venipuncture.
Placebo effect research over the past 15 years has improved our understanding of how placebo treatments reduce patient symptoms. The expectation of symptom improvement is the primary factor underlying the placebo effect. Such expectations are shaped by past experiences, contextual cues and biological traits, which ultimately modulate one’s degree of response to a placebo. The body of evidence that describes the physiology of the placebo effect has been derived from mechanistic studies primarily restricted to the setting of pain. Imaging findings support the role of endogenous opioid and dopaminergic networks in placebo analgesia in both healthy patients as well as patients with painful medical conditions. In patients with psychiatric illnesses such as anxiety disorders or depression, a vast overlap in neurological changes is observed in drug responders and placebo responders supporting the role of serotonergic networks in placebo response. Molecular techniques have been relatively underutilized in understanding the placebo effect until recently. We present an overview of the placebo responder phenotypes and genetic markers that have been associated with the placebo effect in pain, schizophrenia, anxiety disorders and depression.The Pharmacogenomics Journal advance online publication, 22 March 2016; doi:10.1038/tpj.2016.15.
- The journal of pain : official journal of the American Pain Society
- Published over 3 years ago
Placebo analgesia, reductions in pain following administration of an inert treatment, is a well-documented phenomenon. We report the first demonstration that placebo analgesia can be experienced when a sham analgesic is applied onto a rubber hand. The effect was obtained by exploiting the rubber hand illusion, in which ownership is felt over a rubber arm that is unattached to the body. Under conditions of both synchronous and asynchronous visuo-tactile stimulation, a thermal pain stimulus was delivered on the real arm of twenty participants and seemingly also on the rubber arm, before and after applying a sham analgesic and a control cream only to the rubber arm. During synchronous visuo-tactile stimulation, pain was experienced on the rubber arm, and the application of the sham analgesic to the rubber arm significantly decreased the severity of reported pain. This demonstrates that experience of the body can modulate expectations and the induction of placebo analgesia.
Social cues and interpersonal interactions strongly contribute to evoke placebo effects that are pervasive in medicine and depend upon the activation of endogenous modulatory systems. Here, we explore the possibility to boost placebo effects by targeting pharmacologically the vasopressin system, characterized by a sexually dimorphic response and involved in the regulation of human and nonhuman social behaviors.
One-third of cancer patients require opioid rotation (OR) to treat uncontrolled pain or opioid-induced neurotoxicity. Although fentanyl is the most frequently rotated opioid in cancer patients, the accurate opioid rotation ratio (ORR) from transdermal fentanyl (TDF) to other so-called “strong” opioids is unknown.