Traditional Chinese acupuncture and placebo (sham) acupuncture are differentiated by their effects on mu-opioid receptors (MORs)

Abstract

Controversy remains regarding the mechanisms of acupuncture analgesia. A prevailing theory, largely unproven in humans, is that it involves the activation of endogenous opioid antinociceptive systems and mu-opioid receptors (MORs). This is also a neurotransmitter system that mediates the effects of placebo-induced analgesia. This overlap in potential mechanisms may explain the lack of differentiation between traditional acupuncture and either non-traditional or sham acupuncture in multiple controlled clinical trials. We compared both short- and long-term effects of traditional Chinese acupuncture (TA) versus sham acupuncture (SA) treatment on in vivo MOR binding availability in chronic pain patients diagnosed with fibromyalgia (FM). Patients were randomized to receive either TA or SA treatment over the course of 4 weeks. Positron emission tomography (PET) with (11)C-carfentanil was performed once during the first treatment session and then repeated a month later following the eighth treatment. Acupuncture therapy evoked short-term increases in MOR binding potential, in multiple pain and sensory processing regions including the cingulate (dorsal and subgenual), insula, caudate, thalamus, and amygdala. Acupuncture therapy also evoked long-term increases in MOR binding potential in some of the same structures including the cingulate (dorsal and perigenual), caudate, and amygdala. These short- and long-term effects were absent in the sham group where small reductions were observed, an effect more consistent with previous placebo PET studies. Long-term increases in MOR BP following TA were also associated with greater reductions in clinical pain. These findings suggest that divergent MOR processes may mediate clinically relevant analgesic effects for acupuncture and sham acupuncture.

Figure 1

Study Design. A) Participant timeline from consent, through PET imaging sessions, and treatments. Following consent, all participants were randomized to either the traditional acupuncture (TA) or sham acupuncture (SA) treatment groups. Immediately before both PET imaging sessions (i.e. PET1 and PET2), participants completed the SF MPQ to assess clinical pain. During PET1, participants underwent a baseline scan (baseline1) and a treatment scan (treatment1) both of which were used to estimate short-term effects on MOR binding. Participants then received seven acupuncture or sham treatments outside of the scanner. This was followed by PET2, a second imaging session. The baseline scan during PET2 was used for comparison with the baseline scan in PET1 to estimate long-term changes in resting MOR binding. B) TA (red) and SA (black) point locations. Similar body regions were used for both interventions.

Figure 2

Differential Short-Term Effects of Acupuncture and Sham Acupuncture on MOR Binding. A) Regions of interest showing increased MOR BP following acupuncture as compared to sham treatment. upper left: left nucleus accumbens (lNAC), upper right: three thalamic regions (THA), lower left and right: left amygdala (lAMY), and temporal pole (ltmpole) respectively. B) Percent changes and S.E.M. in MOR BP (treatment1 – baseline1) for all regions identified. Red circles (TA) and black circles (SA) represent group mean values with standard error bars. Overall acupuncture resulted in increases in MOR BP with sham treatment resulting largely in either no change or small decreases in BP.

Figure 3

Differential Long-Term Effects of Acupuncture and Sham Acupuncture on MOR Binding. A) Regions of interest showing increased MOR BP following acupuncture as compared to sham treatment. upper left: temporal pole (ltmpole), upper right: dorsal anterior cingulate cortex (dACC), lower left: two perigenual anterior cingulate regions (pgACC). B) Percent changes and S.E.M. in MOR BP (baseline2 –baseline1) for all regions identified. Red circles (TA) and black circles (SA) represent group mean values with standard error bars. Overall acupuncture resulted in an increase in MOR BP whereas sham treatment resulted in either no change or a decrease in binding ability.

Figure 4

Long-term Increases in MOR Binding following Acupuncture are Associated with Reductions in Clinical Pain. A) Regions of interest showing negative correlations between changes in MOR BP (baseline2 – baseline1) and changes in clinical pain (pain assessment2 – pain assessment1) following acupuncture. upper left: left dorsal cingulate cortex (ldCC), upper right: left caudate (lCAU), right putamen (rPUT), and right anterior insula (raIns), lower left: left medial thalamus (lmTHA), lower right: bilateral temporal pole (tmpole). B) Scatter plots of percent changes in MOR BP (post-pre) and changes in clinical pain (post-pre) for four regions depicted in A.