Likar depression, meaning that the risk to induce respiratory arrest does not linearly follow dose-increments of the substance. This ceiling effect provides a safety benefit in case of drug abuse (Doxey et al 1982). A comparison of the respiratory effect of intravenous buprenorphine and fentanyl in both animals and man confirmed a ceiling effect of bupren- orphine, but not for fentanyl. In healthy human volunteers, fentanyl produced a dose-dependent depression of respiration with apnoea at doses ≥ 2.9 µg/kg while respiratory depression caused by buprenorphine levelled off at doses ≥ 3.0 µg/kg (Dahan et al 2005). A dose-response study in healthy male adult volunteers, showed that respiration was maximally depressed at doses of 16 mg of sublingual buprenorphine with a slightly reduced effect at 32 mg. Although 32 mg represents 70 times the recommended analgesic dose, this dose was well tolerated and produced no serious adverse effects (Walsh et al 1994). It is therefore more than unlikely that respiratory depression is caused by buprenorphine in the analgesic dose range. At very high doses (above 32 mg) it could occur. As with other opioids, it can be reversed by the µ-opioid antagonist naloxone, but due to buprenorphine’s very tight binding to opioid receptors and its long-lasting effect, higher and repeated doses of naloxone would be necessary in these rare cases (Dahan et al 2005). Close monitoring of patients’ respiration is recommended, especially in anesthesized or sleeping patients with repeated administration of very high doses of buprenorphine, but this should also be the case with any other µ-opioid agonist. Renal impairment Patients with renal insufficiency frequently require the use of opioids for painful syndromes not responsive to other therapies. This can be a problem particularly in the elderly where age-related changes can affect glomerular filtration, tubular secretion, and reabsorption of metabolites. Changes in renal function may affect the pharmacokinetics of opioids and necessitate a change in dosage (Mercadante and Arcuri 2004). Whilst morphine itself is largely unaffected by renal failure, accumulation of its active metabolite morphine-6- glucuronide cautions its use. Case reports of prolonged narcosis with both codeine and dihydrocodeine in renal insufficiency also call for care when using these agents (Davies et al 1996). The pharmacokinetics of buprenorphine are not altered in patients with renal failure (Summerfield et al 1985; McQuay et al 1986; Moore et al 1994). The main site for metabolism of buprenorphine is the liver, indicating that impaired renal function should have little influence on 120 plasma levels. The major metabolite of buprenorphine is norbuprenorphine. It has been found that levels of this metabolite may be raised after continuous intravenous dosing in patients with renal impairment. However, due to the lower potency and lower affinity of the metabolite for the receptor compared with the parent drug, it is unlikely that this is of any consequence (Hand et al 1990). A recent study of end-stage renal disease patients treated with buprenorphine TDS showed no elevated levels of buprenorphine or norbuprenorphine, indicating that a dose-adaptation in patients with end-stage renal disease is not necessary and analgesic effects of transdermal buprenorphine remain stable during treatment (Filitz et al 2005). Hepatic impairment The liver is the major site of biotransformation for most opioids, which raises the possibility that hepatic insufficiency may lead to reduced drug metabolism and the accumulation in the body. If metabolism is decreased the analgesic effect of the drug may be compromised. The major metabolic pathway for opioids is oxidation, exceptions being morphine and buprenorphine, which undergo glucuronida- tion. It has been shown that although oxidation of opioids is reduced in patients with hepatic cirrhosis resulting in reduced drug clearance, glucuronidation is less affected by liver disease (Tegeder et al 1999). The N-dealkylation of buprenorphine to norbuprenorphine is catalyzed by the cytochrome (CYP) P450 enzyme system, with CYP3A4 being the major isoenzyme. Since CYP3A4 protein expression is reduced in patients with severe chronic liver disease, patients with this condition should be closely monitored during treatment (Tegeder et al 1999). Immunosuppression Suppression of the immune system frequently occurs as a result of the trauma of surgery or from medical conditions such as HIV or cancer. In addition the elderly may be at particular risk due to the progressive declining function of the immune system as a consequence of ageing. Most strong opioids have been found to suppress the immune system to some extent within the antinociceptive range and careful selection of therapeutic agent is important particularly in patients who are already immunocompromised, including cancer patients at risk of metastatic dissemination. The acute administration of morphine has been shown in both animals and humans to significantly reduce cellular immunity and animals treated with morphine have shown an increase in Therapeutics and Clinical Risk Management 2006:2(1)