Likar Buprenorphine, a potent opioid analgesic, has been available in parenteral and sublingual formulations for more than two decades. It offers a number of advantages when compared with morphine and its physicochemical properties make it a suitable candidate for administration in a transdermal preparation. In this paper we will review the safety aspects of long- term opioid therapy and show why and how transdermal buprenorphine is especially suitable for chronic pain management. Buprenorphine Physicochemical properties Buprenorphine is a semi-synthetic derivative of thebaine, one of the chemically most reactive morphine alkaloids. Buprenorphine has a molecular weight of 467 and its structure is typically opioid with the inclusion of a C-7 side- chain containing a t-butyl group. This group confers overall lipophilicity on the molecule which has an important influence on its pharmacology. Opioids exert their pharmacological effects by binding to opioid receptors. The pharmacological effects are determined by the nature of opioid-receptor interaction. Some of these effects such as analgesia, mediated by an agonistic action at the µ-opioid receptor are desirable, whereas others such as nausea, sedation, or constipation can be considered as unwanted adverse effects. Buprenorphine is a µ-opioid receptor agonist with high affinity, but low intrinsic activity. Compared with morphine which behaves as a full µ-opioid agonist, buprenorphine is usually defined as a partial µ-opioid agonist that shows high affinity for and slow dissociation from the µ-opioid receptor. A full dose- dependent effect on analgesia has been seen within the clinically relevant dose range (up to 10 mg), but no respiratory depression which levels off at higher doses (Dahan et al 2005). Clinically, there is also a less marked effect of buprenorphine-binding to µ-opioid receptors on gastrointestinal transit times, and indeed constipation seen in the clinic is remarkably low (Griessinger et al 2005). Buprenorphine also shows partial agonistic activity at the opioid receptor-like receptor 1 (ORL1)-receptors which are (at least at supraspinal receptors) postulated to induce a pronociceptive effect. A study by Lutfy et al (2003) reported that co-activation of ORL1-receptors compromises the antinociception induced by activation of the µ-opioid receptor. ORL1-activation has also an effect on hyperalgesia. It might be that buprenorphine’s partial agonism reduces this effect compared with full ORL1-agonists such as morphine or fentanyl. Buprenorphine’s antagonistic action at the δ-receptors which have a marked anti-opioid action and seem to negatively modulate central analgesia seems further to contribute to its clinically seen analgesic effect. Its likewise antagonistic activity at the κ-opioid receptors might explain the fact that it induces much less sedation and psychotomimetic effects than morphine or fentanyl (Lewis 1985; Leander 1988). Animal studies have shown that buprenorphine has a 20–40 times higher potency than morphine (Martin et al 1976). The strong binding of buprenorphine to the µ-opioid receptor has several consequences. Initial binding is relatively slow compared with other opioids such as fentanyl (Boas and Villiger 1985). However, the onset of analgesia is not dissimilar, since buprenorphine achieves effective analgesia at relatively low receptor occupancy (5%–10%) (Tyers 1980) and thus relatively low plasma concentrations of buprenorphine are sufficient to provide effective pain relief. The slow dissociation of buprenorphine from the receptor results in a long duration of effect and also confers another advantage in that when the drug is withdrawn an abstinence syndrome is rarely seen because of the long time taken for the drug to come off the receptor (Bickel et al 1988). Pharmacokinetics Due to the high first-past effect (95%) seen after oral administration, Buprenorphine was initially available as either a parenteral or sublingual formulation. Onset of analgesia after sublingual administration has been shown to occur within 15 to 45 minutes with peak plasma concentrations reached after two hours (Bullingham et al 1980). The transfer half-life estimated at 76 minutes is consistent with a systemic availability completed within 5 hours. Average bioavailability with sublingual dosing was found to be 55% (McQuay et al 1986). The parenteral formulation of buprenorphine has a speed of onset within 5–15 minutes of either intravenous (IV) or intramuscular (IM) administration. As characteristic of lipophilic compound, buprenorphine exhibits multiphasic clearance; an initial rapid clearance followed by slower clearances observed after IV injection (McQuay and Moore 1995). In the body, buprenorphine is highly protein-bound mostly to α-globulin and β-globulin fractions (Heel et al 1979). Since most drugs bind to albumin, there is no risk of competition for binding proteins, resulting in a lower risk 116 Therapeutics and Clinical Risk Management 2006:2(1)