Dopaminergic tone does not influence pain levels during placebo interventions in patients with chronic neuropathic pain

Abstract

Placebo effects have been reported in patients with chronic neuropathic pain. Expected pain levels and positive emotions are involved in the observed pain relief, but the underlying neurobiology is largely unknown. Patients with neuropathic pain are highly motivated for pain relief, and as motivational factors such as expectations of reward, as well as pain processing in itself, are related to the dopaminergic system, it can be speculated that dopamine release contributes to placebo effects in neuropathic pain. Nineteen patients with neuropathic pain after thoracic surgery were tested during a placebo intervention consisting of open and hidden applications of the pain-relieving agent lidocaine (2 mL) and no treatment. The dopamine antagonist haloperidol (2 mg) and the agonist levodopa/carbidopa (100/25 mg) were administered to test the involvement of dopamine. Expected pain levels, desire for pain relief, and ongoing and evoked pain were assessed on mechanical visual analog scales (0-10). Significant placebo effects on ongoing (P ≤ 0.003) and evoked (P ≤ 0.002) pain were observed. Expectancy and desire accounted for up to 41.2% and 71.5% of the variance in ongoing and evoked pain, respectively, after the open application of lidocaine. We found no evidence for an effect of haloperidol and levodopa/carbidopa on neuropathic pain levels (P = 0.071-0.963). Dopamine seemed to influence the levels of expectancy and desire, yet there was no evidence for indirect or interaction effects on the placebo effect. This is the first study to suggest that dopamine does not contribute to placebo effects in chronic neuropathic pain.

Does conditioned pain modulation predict the magnitude of placebo effects in patients with neuropathic pain?

“…In a recent study, we demonstrated large (Cohen's d = 1.54) and significant (p = 0.002) placebo effects on ongoing neuropathic pain intensity that were highly associated with expectations for pain relief (Skyt et al, 2017). In the present study, we tested the association between the CPM response and the magnitude of the observed placebo effect.…”

“…Although CPM and placebo effects have both been shown to involve the endogenous opioid system (Levine et al, 1978;Willer et al, 1990) and be influenced by expectations (Vase et al, 2005;Lariviere et al, 2007;Bjorkedal and Flaten, 2012;Nir et al, 2012;Cormier et al, 2013;Petersen et al, 2014;France et al, 2016), the impact of these mechanisms is likely to vary. Specifically, expectations seem essential for eliciting placebo effects in neuropathic pain (Petersen et al, 2014;Skyt et al, 2017) but only modestly related to CPM responses (Nir et al, 2012). In addition, several studies suggest that endogenous opioids mediate expectancy-induced placebo effects (Levine et al, 1978;Eippert et al, 2009).…”

“…Secondly, the different roles of expectations might explain the lack of association between the CPM response and the placebo effect. The placebo effect was highly associated with expectations for pain relief (Skyt et al, 2017); yet, we did not assess the influence of expectations on the CPM response, and in future studies, it will be important to directly examine and compare the relative role of expectations in CPM and placebo effects, respectively. A third potential limitation relates to CPM and placebo effects being tested on the same day.…”

Dopaminergic and serotonergic mechanisms in the modulation of pain: In vivo studies in human brain

“…Haloperidol, a dopamine D 2 /D 3 receptor antagonist, had no effects on placebo analgesia at behavioral or neural level, as measured using functional magnetic resonance imaging (Wrobel et al, 2014). In a recent pharmacological study, haloperidol or levodopa failed to influence placebo effect in patients with neuropathic pain, although the level of expectancy was changed (Skyt et al, 2018). Importantly, these studies did not measure striatal dopamine neurotransmission directly, and it is also not known whether higher drug doses would have revealed significant placebo effects.…”

Subliminal (latent) processing of pain and its evolution to conscious awareness

“…These regions may influence brain states in a similar manner as exogenous manipulation, such as anesthetics, may do (Hamilton et al, 2017; Hudetz et al, 2015). Individual differences in subconscious behavior may be mediated by tone/connectivity of reward-aversion systems as they relate to dopaminergic tone and release (Marcott et al, 2014; Skyt et al, 2017) and to individual differences in inhibitory neurotransmitters (Boy et al, 2010). With respect to the latter, it is notable that GABA levels predict responsivity to analgesic efficacy in patients with fibromyalgia (Harris et al, 2013), suggesting an underlying state of pain evolution in these patients.…”