Changes in morphine analgesia and side effects during daily subcutaneous administration in healthy volunteers

Abstract

Tolerance to the anti-nociceptive effects of opioids develops rapidly in animals. In contrast, humans with chronic pain show little or no loss of pain relief in prospective opioid trials of 4-8 weeks duration. Employing the Brief Thermal Sensitization model to induce transient cutaneous secondary hyperalgesia, we tested the hypothesis that opioid analgesic tolerance would develop rapidly. In this outpatient randomized placebo-controlled study, subjects in the MMMMP group received two injections of subcutaneous morphine 6 mg (150 min apart) on Monday-Thursday (total 48 mg over 4 days) and matching saline placebo on Friday. Subjects in the PPPPM group received placebo on Monday-Thursday and morphine (total 12 mg) on Friday. Sixty-one healthy volunteers were enrolled; morphine side effects accounted for all nine non-completions. Compared to the first placebo day, the reduction in the area of secondary hyperalgesia on the first morphine day was significant and robust in both groups. Morphine suppression of the painfulness of skin heating and elevation of the heat pain detection threshold were also significant. During 4 days of twice-daily injections, the decline in anti-hyperalgesic effects of morphine did not reach statistical significance (p=0.06) compared to placebo. Morphine side effects did not correlate with anti-hyperalgesic effects and withdrawal symptoms did not emerge. As 4 days is the threshold for demonstrating analgesic tolerance to twice-daily morphine in animal models, a longer period of opioid exposure in healthy volunteers might be needed to detect analgesic tolerance.

Healthy Volunteers Can Be Phenotyped Using Cutaneous Sensitization Pain Models

“…A total of 342 subjects, with 409 repeated measurements, were included in the analyses of the ten studies (Table 1) ([2], [4]–[8], [11]–[13], unpublished data). Five studies used only the heat/capsaicin model (n = 122) ([2], [4]–[6], unpublished data), one study used only the brief thermal sensitization model (n = 53) [11], one study used only the burn injury model (n = 100) [12] and in three studies subjects underwent both the H/C and BTS model (n = 67) [7], [8], [13].…”

“…Data was obtained from ten studies (9 published [2], [4]–[8], [11]–[13] and 1 unpublished [Petersen et al, unpublished data]) of healthy volunteers (conducted in Copenhagen or San Francisco) in which experimental cutaneous secondary hyperalgesia was induced on two or more study days, and in which the area of secondary hyperalgesia to monofilament stimulation was the primary outcome measure (Table 1). Three different pain models were used: the heat/capsaicin sensitization (H/C) model, the brief thermal sensitization (BTS) model and the burn-injury (BI) model.…”

“…Three different pain models were used: the heat/capsaicin sensitization (H/C) model, the brief thermal sensitization (BTS) model and the burn-injury (BI) model. In the ten studies, five used only the H/C model ([2], [4]–[6], unpublished data), one used the BTS model [11], and one study used the BI model [12]. In three studies subjects underwent both testing with the H/C and BTS model [7], [8], [13].…”

“…In six studies heat stimuli were delivered by a MSA thermode (Somedic AB, Hörby, Sweden [size 2.5×5.0 cm 2 ]) [2], [4]–[7], [12], [13] and in four studies by a TSA 2001 thermode (Medoc, Ramat Yishai, Israel [size 3.2×4.8 cm 2 ])( [4], [11], unpublished data). All procedures were performed with subjects resting head up on a hospital bed, or sitting comfortably in a chair with their arm on the armrest.…”

“…In all but one study the borders of secondary hyperalgesia were determined by stimulating with a monofilament (20.9 g [4], 21.5 g [2], [5]–[7], [13], 26.0 g [8], [11]), along 4 linear paths arranged in 90° angles around the stimulation center, in 5-mm steps at 1-s intervals. Stimulation along each path started well outside the hyperalgesic area and continued toward the stimulated skin area.…”