Effect of transdermal opioids in experimentally induced superficial, deep and hyperalgesic pain

Abstract

BACKGROUND AND PURPOSE Chronic pain and hyperalgesia can be difficult to treat with classical opioids acting predominately at the µ‐opioid receptor. Buprenorphine and its active metabolite are believed to act through µ‐, κ‐ and δ‐receptors and may therefore possess different analgesic and anti‐hyperalgesic effects compared with pure µ‐receptor agonists, for example, fentanyl. Here, we have compared the analgesic and anti‐hyperalgesic effects of buprenorphine and fentanyl. EXPERIMENTAL APPROACH Twenty‐two healthy volunteers were randomized to treatment with transdermal buprenorphine (20 µg·h−1, 144 h), fentanyl (25 µg·h−1, 72 h) or placebo patches in a double‐blind, cross‐over experimental pain study. The experimental pain tests (phasic pain, sensitization) involved pressure at the tibial bone, cutaneous electrical and thermal stimulation, intramuscular nerve growth factor, UVB light burn injury model and intradermal capsaicin‐induced hyperalgesia. Pain testing was carried out at baseline, 24, 48, 72 and 144 h after application of the drugs. KEY RESULTS Compared with placebo, buprenorphine, but not fentanyl, significantly attenuated pressure at the tibial bone as well as pressure pain in the primary hyperalgesic area induced by UVB light The two drugs were equipotent and better than placebo against cutaneous thermal pain stimulation), but failed to show significant analgesic effect to cutaneous electrical stimulation, nerve growth factor‐induced muscle soreness and to capsaicin‐induced hyperalgesia. CONCLUSIONS AND IMPLICATIONS Buprenorphine, but not fentanyl, showed analgesic effects against experimentally induced, bone‐associated pain and primary hyperalgesia compared with placebo. These tissue‐ and modality‐differentiated properties may reflect the variable effects of opioid drugs observed in individual patients.

Human Experimental Pain Models for Assessing the Therapeutic Efficacy of Analgesic Drugs

“…In evaluation of analgesics, most studies have applied models in the skin, but from a clinical perspective, deep pain and models in which hyperalgesia and allodynia is evoked are more relevant. Subsequently, reliable and valid pain models from muscle, bone, and viscera have been developed together with chemical models evoking hyperalgesia Arendt-Nielsen et al, 2007a;Olesen et al, 2009b;Staahl et al, 2009a;Andresen et al, 2010). This mimics the clinical situation to a better extent, and in these models the effects of analgesics have been consistently reported (Koppert et al, 2005;Olesen et al, 2010a).…”

“…The advantage is that the model has been used in assessment of analgesics (Andresen et al, 2010), and it has been shown that the model is reproducible with minor pain component of the overlying skin (T. Andresen, M. P. Jensen, C. Brock, A. M. Drewes, L. ArendtNielsen, unpublished observations).…”

“…Intramuscular injection of NGF has been shown to induce long-term sensitization and time-dependent hyperalgesia, indicating potential involvement of both central and peripheral pain mechanisms (Andersen et al, 2008). NGF has been used in both basic pain studies and in studies investigating analgesic effects, and has been injected into, for example, the extensor digitor longus muscle (Andresen et al, 2010), the middle of the muscle belly of the tibialis anterior (Andersen et al, 2008) or the masseter muscle . The model has been shown to induce long-lasting, pressure-evoked soreness of the muscle and time-dependent pressure hyperalgesia, most likely involving peripheral and central mechanisms, and is applicable in testing of analgesics (Andresen et al, 2010).…”

“…NGF has been used in both basic pain studies and in studies investigating analgesic effects, and has been injected into, for example, the extensor digitor longus muscle (Andresen et al, 2010), the middle of the muscle belly of the tibialis anterior (Andersen et al, 2008) or the masseter muscle . The model has been shown to induce long-lasting, pressure-evoked soreness of the muscle and time-dependent pressure hyperalgesia, most likely involving peripheral and central mechanisms, and is applicable in testing of analgesics (Andresen et al, 2010). The effect of NGF on muscle contraction can also be tested, and this has been done by use of a custommade shoe with 3 kg attached distally, leading to muscle hyperalgesia to distant areas, indicating involvement of central mechanisms (Andersen et al, 2008).…”

“…The model is best used in studies of compounds with a peak analgesic effect time of 2 to 3 h because of the duration of the cutaneous sensitization (Dirks et al, 2003;Andresen et al, 2010;Modir and Wallace, 2010). Andresen et al (2010) further demon-736 strated that red-haired women were less sensitized to capsaicin-induced hyperalgesia compared with blond/ dark haired women, which could be important in future studies investigating antihyperalgesic drugs as well as treatment of pain.…”