Relationship Between Endogenous Opioid Function and Opioid Analgesic Adverse Effects

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Background and Objectives

Our recent work indicates that endogenous opioid activity influences analgesic responses to opioid medications. This secondary analysis evaluated whether endogenous opioid activity is associated with degree of opioid analgesic adverse effects, and whether chronic pain status and sex affect these adverse effects.


Using a double-blind, randomized, placebo-controlled, crossover design, 51 subjects with chronic low back pain and 38 healthy controls participated in 3 separate sessions, undergoing 2 laboratory-evoked pain tasks (ischemic and thermal) after receiving placebo, naloxone, or morphine. Endogenous opioid system function was indexed by the difference in pain responses between the placebo and naloxone conditions. These measures were examined for associations with morphine-related adverse effects.


Chronic pain subjects reported significantly greater itching and unpleasant bodily sensations with morphine than controls (P < 0.05). Across groups, only 6 of 112 possible associations between adverse effects and blockade effects were significant. For the ischemic task, higher endogenous opioid function was associated with greater itching (visual analog scale [VAS]; P < 0.05), numbness (tolerance; P < 0.001), dry mouth (tolerance; P < 0.05), and unpleasant bodily sensations (VAS; P < 0.05). For the thermal task, higher endogenous opioid function was associated with greater numbness (VAS; P < 0.05) and feeling carefree (VAS; P < 0.05). There were no significant main or interaction effects of chronic pain status or sex on these findings.


No consistent relationships were observed between endogenous opioid function and morphine-related adverse effects. This is in stark contrast to our previous observation of strong relationships between elevated endogenous opioid function and smaller morphine analgesic effects.

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