Buprenorphine, an opioid with mixed agonist-antagonist activity at classical opioid receptors, has been approved recently for the treatment of opioid dependency. Buprenorphine is also used as an analgesic. The buprenorphine dose-response curve is sometimes submaximal, or even bell-shaped, in nociceptive assays, depending upon the nature and intensity of the noxious stimulus. Moreover, buprenorphine, when administered with full agonists, such as morphine, antagonizes the action of these drugs. Partial agonism at the mu opioid receptor and, in some cases, antagonism at the kappa or delta opioid receptor have been considered as possible underlying mechanisms for the ceiling effect and bell-shaped dose-response curve of buprenorphine. While ceiling effects can be explained by partial agonist activity of buprenorphine, the bell-shaped dose-response curve cannot be a consequence of this property of the drug. Recently, buprenorphine has been shown to activate the opioid receptor-like (ORL-1; also known as NOP) receptor. Supraspinal activation of the ORL-1 receptor counteracts the antinociceptive and rewarding actions of morphine, raising the possibility that these actions of buprenorphine can also be altered by its ability to concomitantly activate the ORL-1 receptor. The use of molecular biological techniques has advanced our knowledge regarding the role of opioid receptors in modulation of pain and reward. In particular, generation of opioid receptor knockout mice has proven useful in this regard. Indeed, using knockout mice, we have recently shown that the antinociceptive effect of buprenorphine mediated primarily by the mu opioid receptor is attenuated by the ability of the drug to activate the ORL-1 receptor. Thus, the goal of this review is to provide evidence demonstrating that the ORL-1 receptor plays a functional role not only in the antinociceptive effect of buprenorphine but also in other actions of the drug as well.

/pdf/buprenorphine-a-unique-drug-with-complex-pharmacology-87p9ascn8b.pdf

Buprenorphine: a unique drug with complex pharmacology.

Recent observations on the steroid synthetic capability within the brain open the possibility that benzodiazepines may influence steroid synthesis in nervous tissue through interactions with peripheral-type benzodiazepine recognition sites, which are highly expressed in steroidogenic cells and associated with the outer mitochondrial membrane. To examine this possibility nine molecules that exhibit a greater than 10,000-fold difference in their affinities for peripheral-type benzodiazepine binding sites were tested for their effects on a well-established steroidogenic model system, the Y-1 mouse adrenal tumor cell line. 4'-Chlorodiazepam, PK 11195, and PK 14067 stimulated steroid production by 2-fold in Y-1 cells, whereas diazepam, flunitrazepam, zolpidem, and PK 14068 displayed a lower (1.2- to 1.5-fold) maximal stimulation. In contrast, clonazepam and flumazenil did not stimulate steroid synthesis. The potencies of these compounds to inhibit 3H-labeled PK 11195 binding to peripheral-type benzodiazepine recognition sites correlated (r = 0.985) with their potencies to stimulate steroid production. Similar findings were observed in bovine and rat adrenocortical cell preparations. These results suggest that ligands of the peripheral-type benzodiazepine recognition site acting on this mitochondrial receptor can enhance steroid production. This action may contribute specificity to the pharmacological profile of drugs preferentially acting on the benzodiazepine recognition site associated with the outer membrane of certain mitochondrial populations.

Mitochondrial benzodiazepine receptors regulate steroid biosynthesis.

Fentanyl is a synthetic opioid with short-acting analgesic activity after intravenous or subcutaneous administration. The low molecular weight, high potency and lipid solubility of fentanyl make it suitable for delivery via the transdermal therapeutic system (TTS). These systems are designed to release the drug into the skin at a constant rate ranging from 25 to 100 micrograms/h, multiple systems can be applied to achieve higher delivery rates. Initially, much of the clinical experience with fentanyl TTS was obtained in patients with acute postoperative pain. However, because of the increased risk of respiratory complications, fentanyl TTS is contraindicated in this setting. Fentanyl TTS is recommended for use in chronic cancer pain. Moreover, in 11 countries worldwide including the US, its use is not restricted to chronic cancer pain; the drug is also available for treatment of general chronic pain, including that of nonmalignant origin. At the start of fentanyl TTS treatment, depot accumulation of the drug within skin tissue results in a significant delay (17 to 48 hours) before maximum plasma concentration is achieved. Approximately half of the cancer patients converted to transdermal fentanyl from other opioid agents required increased dosages after initial application of the patch. However, concomitant use of short-acting morphine maintained pain relief during the titration period, and the use of such supplementary medication decreased with the duration of fentanyl TTS treatment. In patients with chronic cancer pain, changes in visual analogue scale (VAS) pain scores ranged from a 10% increase (worse pain) to > 50% decrease (less pain) during transdermal fentanyl therapy compared with previous opioid treatment. In addition, patient preference for fentanyl TTS was indicated by the number of patient requests (up to 95%) for continued use of the drug at the end of the study. Although fentanyl TTS is contraindicated in patients postoperatively, the efficacy of fentanyl via the transdermal route was investigated in this patient group. Supplementary patient controlled analgesia was significantly reduced in patients who received fentanyl TTS 75 micrograms/h compared with placebo, although this was not apparent until > or = 12 hours after application. Data evaluating pain relief, which was assessed by VAS pain scores, were inconclusive. Preliminary data, although from relatively small numbers of patients, indicate that transdermal fentanyl may be useful in the management of chronic non-malignant pain. Indeed, some patients whose pain was previously uncontrolled became completely pain free. The most frequently occurring adverse events during fentanyl TTS therapy (as with other opioid agents) included vomiting, nausea and constipation, although vomiting and nausea were not clearly associated with the drug. The most serious adverse event was hypoventilation, which occurred more frequently in postoperative (4%) than in cancer patients (2%). In surgical patients, fentanyl-associated respiratory events (reduced respiratory rate and apnoea) generally occurred within 24 hours of patch application; however, there were isolated reports of late onset (> or = 36 hours postsurgery) fentanyl-associated respiratory depression. In cancer patients, the incidence of constipation was reduced by up to two-thirds after switching from oral morphine to transdermal fentanyl. Transient skin irritation associated with the plastic patch or the adhesive, rather than the drug, was reported in a maximum 3% of patients. In summary, transdermal fentanyl is a useful alternative to other opioid agents, which are also recommended on the third step of the WHO analgesic ladder, in the management of chronic malignant pain. Preliminary data indicate that it may be useful in the management of chronic nonmalignant pain. The advantages offered by fentanyl TTS over traditional methods of chronic pain control include its ease of administration, less constipation and the 3-

Transdermal fentanyl. A review of its pharmacological properties and therapeutic efficacy in pain control.

Fentanyl is a synthetic opioid agonist which interacts primarily with the μ-opioid receptor. The low molecular weight, high potency and lipid solubility of fentanyl make it suitable for delivery by the transdermal therapeutic system. These patches are designed to deliver fentanyl at a constant rate (25, 50, 75 and 100 μg/h). and require replacement every 3 days. Data from randomised, nonblind trials suggest that transdermal fentanyl is as effective as sustained-release oral morphine in the treatment of chronic cancer pain, as reported by patients using visual and numerical analogue scales as well as verbal description scales. No obvious differences in health-related quality of life were found in patients with chronic cancer pain when comparing transdermal fentanyl with sustained-release oral morphine. Nevertheless, significantly more patients expressed a preference for transdermal fentanyl than for sustained-release oral morphine after a randomised, nonblind, crossover trial. Because of the formation of a fentanyl depot in the skin tissue, serum fentanyl concentrations increase gradually following initial application, generally levelling off between 12 and 24 hours. Thereafter, they remain relatively constant, with some fluctuation, for the remainder of the 72-hour application period. Once achieved, steady-state plasma fentanyl concentrations can be maintained for as long as the patches are renewed. The most frequently observed adverse events during transdermal fentanyl administration (as with other opioid agonists) included vomiting, nausea and constipation. Data from a nonblind, randomised trials suggest that constipation occurs less frequently in patients receiving transdermal fentanyl than in those given sustained-release oral morphine. The most serious adverse event reported in US premarketing trials was hypoventilation, which occurred with an incidence of approximately 2%. Adverse reactions related to skin and appendages (i.e. rash and application site reactions - erythema, papules, itching and oedema) were reported in 153 patients with cancer at a frequency between I and 3%. Conclusion: Transdermal fentanyl is a useful opioid-agonist for the treatment of moderate to severe chronic cancer pain. The advantages of transdermal fentanyl include ease of administration and the 3-day application interval. These factors coupled with a lower incidence of constipation are likely to contribute to the reported patient preference of transdermal fentanyl over sustained-release oral morphine. Fentanyl interacts with the μ-opioid receptor as a pure agonist. The analgesic potency of fentanyl is 75 to 100 times higher than that of morphine, probably because fentanyl is lipophilic, allowing rapid penetration of the blood-brain barrier. The mechanisms of opioid-induced analgesia are only partly understood. Like other opioid agonists, fentanyl can induce potentially life-threatening respiratory depression. Experiments in cats suggest that fentanyl-induced sustained inspiration (thoracic rigidity) results from increased amplified efferent activity to the spinal cord inspiratory motor neurons. Moreover, studies in rats suggest that fentanyl, unlike morphine, induces respiratory depression via the μ 1 -receptor. Constipation is a common adverse event after opioid administration. Subcutaneous administration of fentanyl and morphine to rats resulted in an analgesic peak effect at doses of 0.032 mg/kg and 8.0 mg/kg, respectively.

Transdermal fentanyl: an updated review of its pharmacological properties and therapeutic efficacy in chronic cancer pain control.

Receptor binding assays were undertaken in an attempt to elucidate the opioid binding characteristics of fentanyl and buprenorphine, and to investigate some of the differences between them. Buprenorphine showed slow receptor association (30 min), but with high affinity to multiple sites from which dissociation was very slow (T½ = 166 min) and incomplete (50% binding after 1 h). This contrasted with the receptor binding of fentanyl, which achieved rapid equilibrium (within 10 min) and dissociated equally rapidly (T½ = 6.8 min) and completely (100% by 1 h). Competitive displacement showed buprenorphine displacement of fentanyl binding was concentration-and time-dependent over ranges encountered in clinical use, but buprenorphine binding was displaced with only very high concentrations of other opioids. These findings offer pharmacodynamic explanations for the differences in fentanyl and buprenorphine analgesic response profiles and suggest how binding interactions might be applied to therapeutic use.

J.W. Villiger

Papers

Characteristics of [3H]fentanyl binding to the opiate receptor

Binding of buprenorphine to opiate receptors: Regulation by guanyl nucleotides and metal ions

Characterization of peripheral-type benzodiazepine recognition sites in the rat spinal cord.

Specific [3H]neurotensin binding to rat spinal cord membranes