Likar binding sites on plasma proteins such as albumin and α- or γ-globulins may cause reduced binding and hence increased levels of unbound drug, which may cause an increased pharmacological effect. The pharmacological profile of buprenorphine is favourable in this respect since 96% is bound to α- or γ-globulins whereas most other drugs bind to albumin. Many drugs are metabolised in the liver by the cytochrome P450 system and those that act as either inducers or inhibitors of this enzyme system may cause clinically important drug interactions. Buprenorphine has been demonstrated to inhibit CYP3A4- and CYP2D6-mediated reactions, however, at therapeutic concentrations it is unlikely that either buprenorphine or its metabolite norbuprenorphine would cause significant interactions with other CYP-metabolised drugs (Umehara et al 2002; Zhang et al 2003). However, all opioids interact with other CNS-depressant drugs, eg, benzodiazepines, and this might result in an increased risk of centrally-mediated side effects such as sedation or respiratory depression. This effect is most likely due to a synergistic pharmacodynamic effect on the CNS and not to hepatic metabolism (Ibrahim 2000). There is a respective class label warning in the summary of product characteristics (SmPCs) of transdermal buprenorphine and of all other strong opioids. Dependence, addiction, and abuse potential Fear of dependence and addiction is one of the main reasons why many clinicians have in the past been reluctant to prescribe opioids. As a drug class, therapeutic doses of opioids are safe and non-toxic even under chronic dosing conditions. Supratherapeutic doses of µ-opioid agonists can be lethal, especially when administered to non-tolerant individuals. This toxicity is mainly due to the respiratory depressant action. As previously discussed, in contrast to many other opioids buprenorphine shows a ceiling effect with respect to respiratory depression that contributes to its safety profile. Reports of episodic cases of buprenorphine abuse have largely been confined to experienced drug abusers. The abuse potential of buprenorphine, although low, is further reduced in a transdermal preparation because the plasma levels slowly rise to a therapeutic level, unlike the rapid peak level that occurs with other formulations. There is little evidence that buprenorphine has the potential to cause dependence and addiction. Even after prolonged treatment with buprenorphine withdrawal symptoms after spontaneous withdrawal are relatively 122 moderate compared with those that occur after comparable treatment schedules with opioids such as morphine, fentanyl, or methadone (Tzschentke 2002; Walsh and Eissenberg 2003). This property is probably related to the receptor kinetics of the drug, as dissociation occurs very slowly once bound to the µ-opioid receptor. The long duration of action of buprenorphine (and hence need for less frequent dosing) has suggested its use in the treatment of opioid addiction. Buprenorphine has been shown to be capable of blocking the effects of 120 mg doses of morphine, a blockage that persisted for 29.5 hours (Jasinski et al 1978). Buprenorphine in sublingual form has been found to be acceptable to addicts, and its limited withdrawal effects makes a gradual reduction in the dose of buprenorphine taken more likely. The advantages of transdermal buprenorphine for long-term therapy The treatment of chronic pain frequently requires long-term therapy that may continue for many months or even years. Transdermal buprenorphine offers an easy to use formulation which can maintain therapeutic serum levels for up to 96 hours. The availability of sublingual buprenorphine tablets for use as supplementary medication in breakthrough pain episodes is in line with the WHO recommendation for an immediate release formulation containing the same substance for rapid pain relief if required. In terms of handling, transdermal buprenorphine offers a number of advantages. The patch can be applied by the patient or carer, it is unobtrusive and sticks on well over the full dosage period. In a study of 239 chronic pain patients who used buprenorphine TDS for a mean period of 7.5 months, 93.3% rated handling of the patch as “without problem” (Likar et al 2005). Buprenorphine TDS can be used by patients with swallowing difficulties and results in less tablet intake, an important feature for the elderly who may need mostly orally applied co-medication. It should be kept in mind that due to buprenorphine’s high affinity for the µ-opioid receptor and its long duration of action, newly applied analgesics may not work until the clinically relevant doses of buprenorphine level off after the final removal of buprenorphine patches. During continuous therapy with buprenorphine patches, this long duration of action of buprenorphine is not a problem as the newly applied buprenorphine patches need 12–24 hours until clinically relevant plasma levels are reached. Analgesic gaps are therefore unlikely as long as proposed dosing schemes are followed, and transdermal bupren- Therapeutics and Clinical Risk Management 2006:2(1)