Venlafaxine and oxycodone have different effects on spinal and supraspinal activity in man: a somatosensory evoked potential study

Abstract

AIMSOpioids and antidepressants that inhibit serotonin and norepinephrine reuptake (SNRI) are recognized as analgesics to treat severe and moderate pain, but their mechanisms of action in humans remain unclear. The present study aimed to explore how oxycodone (an opioid) and venlafaxine (an SNRI) modulate spinal and supraspinal sensory processing. METHODSTwenty volunteers were included in a randomized, double-blinded, three-way (placebo, oxycodone, venlafaxine), crossover study. Spinal and full scalp cortical evoked potentials (EPs) to median nerve stimulation were recorded before and after 5 days of treatment. Assessment of the central effects of the three treatments involved: (i) amplitudes and latencies of spinal EPs (spinal level); (ii) amplitudes and latencies of the P14 potential (subcortical level); (iii) amplitudes and latencies of early and late cortical EPs (cortical level); (iv) brain sources underlying early cortical Eps; and (v) brain networks underlying the late cortical EPs. RESULTSIn the venlafaxine arm, the spinal P11 and the late cortical N60-80 latencies were reduced by 1.8% [95% confidence interval (CI) 1.7%, 1.9%) and 5.7% (95% CI 5.3%, 6.1%), whereas the early cortical P25 amplitude was decreased by 7.1% (95%CI 6.1%, 8.7%). Oxycodone increased the subcortical P14 [+25% (95% CI 22.2%, 28.6%)], early cortical N30 [+12.9% (95% CI 12.5%, 13.2%)] amplitudes and the late cortical N60-80 latency [+2.9% (95% CI 1.9%, 4.0%)]. The brainstem and primary somatosensory cortex source strengths were increased by 66.7% (95% CI 62.5%, 75.0%) and 28.8% (95% CI 27.5%, 29.6%) in the oxycodone arm, whereas the primary somatosensory cortex strength was decreased in the venlafaxine arm by 18.3% (95% CI 12.0%, 28.1%). CONCLUSIONS WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Opioids and antidepressant drugs with an effect on serotonin and norepinephrine reuptake inhibition (SNRI) are used in chronic pain but their mechanisms in humans remain unclear.• Central changes in the brain due to opioid analgesia have been observed before.• The antinociceptive effects of SNRI drugs have previously been demonstrated in animal models. WHAT THIS STUDY ADDS• Venlafaxine induced changes at the spinal and cortical levels, whereas oxycodone induced changes at the brainstem and cortical levels.• The cortical modifications were different between venlafaxine and oxycodone.• The study contributes to the much-needed human models of the mechanisms of action of drugs with effects on the central nervous system. Tables of Links

Differential effects of oxycodone and venlafaxine on resting state functional connectivity—A randomized placebo‐controlled magnetic resonance imaging study

“…We also found venlafaxine to reduce functional connectivity to parietal regions. Additionally, using the same cohort of healthy volunteers as in the present study, in our previous EEG study involving spinal and cortical evoked potentials, we observed a decrease in latencies induced by venlafaxine treatment, and in an EEG study involving tonic pain, we observed a decrease in alpha activity induced by venlafaxine treatment, which was correlated to decrease in pain scores . The observed changes in the surface EEG could be related to changes in functional connectivity observed in our present MRI study.…”

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“…Early cortical activation was analysed at the negative potential (N20) and the positive potential (P22), at the centro‐parietal CP5 electrode contralateral to the stimulation, and the peak‐to‐peak amplitude was used. In a similar way the latencies and amplitude of the subcortical response (N14‐P18) was analysed at the occipital midline electrode (Oz), and late cortical response (N60‐P80) was assessed at the central midline electrode C1 …”

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“…In this regard, there are several potential confounders for the neurophysiological testing (eg, NWR) including diabetes and analgesics that may influence our results such as recently shown by our group. 28,49,50 We did, however, take this partly into account since we stratified for opioid use in our analysis. Due to the relatively small sample size, the validity of the correlation analyses may be limited, and there was an overall increased risk of type 2 errors.…”