Modulation of remifentanil-induced postinfusion hyperalgesia by the β-blocker propranolol in humans

Abstract

Acute and chronic exposure to opioids has been associated with hyperalgesia in both animals and humans. A genetic analysis of opioid-induced hyperalgesia in mice linked the β(2)-adrenergic receptor to mechanical sensitization after opioid exposure. In humans, expansion of the area of mechanical hyperalgesia surrounding an experimentally induced lesion after the cessation of remifentanil infusion is a commonly used model of opioid hyperalgesia (remifentanil-induced postinfusion hyperalgesia, RPH). The purpose of our translational study was to test the hypothesis that the β-adrenergic receptor antagonist propranolol modulates the expression of RPH in humans. This double-blinded, randomized, placebo-controlled, crossover study was performed in 10 healthy human volunteers. During test sessions, intracutaneous electrical stimulation was used to generate areas of secondary mechanical hyperalgesia. The area of this sensitization was measured before, during, and after remifentanil infusion. Heat pain sensitivity was also followed. During one test session, subjects received propranolol infusion. We observed an average increase in the areas of secondary mechanical hyperalgesia to 141% of the baseline in subjects infused with remifentanil and placebo (P=0.00040). However, when remifentanil infusion was combined with propranolol, the area of secondary hyperalgesia after terminating remifentanil was not significantly different than the area before beginning the opioid infusion (P=0.13). Thermal hyperalgesia was not observed after remifentanil infusion. Propranolol infusion at the selected dose had minor hemodynamic effects. Concomitant infusion of propranolol with remifentanil prevented the expression of RPH. β-adrenergic receptor blockade may be a useful pharmacological strategy for preventing hyperalgesia in patients exposed to opioids.

Targeting Opioid-Induced Hyperalgesia in Clinical Treatment: Neurobiological Considerations

“…Ackerman [40] described a similar outcome in 28 % of a sample of 197 patients with chronic pain receiving opioids. While some studies suggest that OIH develops after chronic opioid use [41][42][43], both rodent [44,45] and human studies [46][47][48][49] have documented OIH within hours of acute opioid administration. Studies using shorter-acting opioids such as remifentanil, sufentanil, fentanyl, and morphine provide the most suspicion of OIH [49][50][51][52][53][54][55][56]; however, there is documentation of this phenomenon in patients receiving long-acting opioids (e.g., methadone or buprenorphine) as well [23,43,[57][58][59][60].…”

“…Following the results of a genetic study linking the b-adrenergic receptor to OIH [210], speculation arose regarding the clinical therapeutic effect of propranolol in treating OIH. Accordingly, Chu et al [47] conducted a clinical trial in which propranolol effectively eliminated secondary hyperalgesia in healthy volunteers receiving remifentanil infusion and undergoing experimental pain testing ( Table 3). As such, propranolol may prove useful in precluding OIH; however, further studies are needed.…”

Intrathecal injection of KN93 attenuates paradoxical remifentanil-induced postoperative hyperalgesia by inhibiting spinal CaMKII phosphorylation in rats

“…It provides adequate and controllable analgesia, and has a rapid onset of action without accumulation effects after intravenous infusion (Bürkle et al, 1996). However, experimental and clinical studies implied that remifentanil might induce hyperalgesia after surgery, or worsen postoperative pains (Joly et al, 2005;Troster et al, 2006;Singler et al, 2007;Chu et al, 2012). Guignard et al (2000) found that hyperalgesia occurred in patients with colon surgery after infusion of remifentanil at 6 μg/kg and 18 μg/kg.…”

The Netrin-1 receptor DCC is a regulator of maladaptive responses to chronic morphine administration

“…We expect genetic approaches in mice to also be informative, since there are very large differences in the response of inbred strains to opiates, including the development of opioid analgesia, tolerance, dependence and hyperalgesia [8–14]. In fact, HBCGM, which used SNP databases generated from limited sequence information, has identified several involved genes including those coding for β2-adrenergic and 5-HT3 receptors that affect opiate responses, and these findings were translated to humans [8, 15]. …”