Effect of Intravenous Alfentanil on Nonpainful Thermally Induced Hyperalgesia in Healthy Volunteers

Abstract

Experimental interventions that activate specific components of clinical pain are necessary for characterization of underlying mechanisms and pharmacology. Cutaneous hyperalgesia has been described that uses non-painful heat to induce secondary hyperalgesia. This study evaluated the effect intravenous alfentanil on experimental cutaneous hyperalgesia created using this method. Eighteen subjects participated in a randomized, double-blinded, placebo controlled crossover study consisting of two sessions, one with alfentanil and one with placebo. Using a computer-controlled infusion pump, alfentanil or matching placebo was maintained at a constant plasma level of 75 ng/ml for one hour followed by the application of a 40° C heat stimulus to the right thenar eminence for 15 minutes. The temperature was raised by 1° C every 15 minutes until the subject reported pain or 45° C was reached. After the end point was reached, the temperature was maintained and repeat testing was performed. The non-painful heat created an area of secondary cutaneous hyperalgesia and significant decrease in mechanical pain threshold on heat-treated right versus untreated left during placebo administration. Alfentanil prevented the hypersensitivity when compared to placebo (p<0.05), but failed to reduce the area of secondary hyperalgesia created by non-painful heat when compared to placebo (p=0.06). Neither alfentanil nor the heat lamp treatment showed any significant effect on other neurosensory measures. This study demonstrated a reliable production of cutaneous hyperalgesia using a non-painful stimulus that is affected by the systemic delivery of alfentanil. This model for human cutaneous experimental pain may be a useful method for scientific characterization of analgesics.

Human surrogate models of central sensitization: A critical review and practical guide

“…Initial techniques using small skin spots at >50°C on glabrous skin were instrumental in clarifying many aspects of peripheral encoding of heat pain (Meyer & Campbell, 1981 ; Raja et al., 1984 ) (Table 3 ), but produced second degree burns, blisters and visible oedema, and have been replaced by techniques using lower temperatures on hairy skin. Prolonged thermal stimulation at non‐painful levels (40–42°C) can also trigger secondary hyperalgesia; however, the stimulus has to be maintained for long periods, and hyperalgesia is extremely short‐lived (Cervero et al., 1993 ; Schifftner et al., 2017 ). Therefore, most studies used thermodes at higher temperatures (~47°C) applied during 5–7 min to a 9–16 cm 2 hairy skin contact area (Table 3 ).…”

“…Thermode‐induced 2HA was decreased by systemic opioids including morphine, buprenorphine and alfentanil in seven studies (six controlled; Table 6 ), but failed to overpower placebo in four controlled trials (Lillesø et al., 2000 ; Ravn et al., 2014 ; Schifftner et al., 2017 ; Warncke et al., 1997 ). Gabapentin decreased 2HA in two controlled studies (Dirks et al., 2002 ; Petersen et al., 2014 ) and showed a trend in a third one ( p =.06; Werner et al., 2001 ).…”

“…Areas of hyperalgesia/allodynia have been the most frequently used readouts, and are often correlated with the evoked pain within the hyperalgesic region. However, these two variables can also be dissociated (Ando et al., 2000 ; Schifftner et al., 2017 ; Zheng et al., 2009 ), and pain within the hyperalgesic region has been reported as more reliable than area size to tag clinically useful analgesia (Ando et al., 2000 ; Lötsch et al., 2020 ). Quantifying pain intensity is more subjective and prone to bias than measuring the area of hyperalgesia, which is performed without visual control from subjects (Jensen & Petersen, 2006 ).…”

Effects of single-use alfentanil versus propofol on cognitive functions after colonoscopy: A randomized controlled trial

“…The incidence of respiratory depression was low in both groups. Alfentanil inhibits breathing to a lesser extent than other opioids and has a lower incidence of choking [ 38 ]. Pre-oxygenation and slow bolus administration can reduce respiratory depression.…”

Opioid-induced Hyperalgesia: Myth or Burgeoning Public Health Crisis

“…There continues to be debate regarding this somewhat elusive condition and its legitimacy as clinical entity requiring attention and treatment. Most studies conducted in humans revolve around rapid-acting intravenous opioids such as alfentanil (7) and remifentanil (8), in acute hyperalgesic states created experimentally (1), or else in recovering drug addicts, and have not been as precise in defining the role of OIH with chronic oral consumption of opioids. Electrophysiological studies have shown that remifentanil elicits rapid and prolonged upregulation of N-methyl-D-aspartate receptor (NMDAR) currents, which may contribute to the development of OIH.…”