1 Newlands, Chevin Avenue, Menston, Ilkley LS29 6E, West Yorkshire, UK E-mail: keithbudd{at}tiscali.co.uk 2 Pain Management Centre, Leicester Royal Infirmary, Leicester LE1 5WW, UK E-mail: wreake{at}aol.com
Declaration of interest. Dr Collett was a member of the Transtec Advisory Board (two Meetings) organised by Napp Pharmaceuticals and has been in receipt of three travel grants from that company over the last 5 years. Dr Budd was a member of the Transtec Advisory Boards of Napp Pharmaceuticals and Grunenthal GmbH and has received lecture and travel expenses from both companies.
Buprenorphine has been an enigmatic opioid since it was first launched for clinical use in 1979. Whilst having significant potential as a strong opioid, perhaps even rivalling morphine, it has never achieved the promising future predicted for it. Why?
The main problem appears to be that a number of misconceptions arose early in buprenorphines pre-clinical and clinical exposure relating to a lack of scientific studies in specific areas of its pharmacological activity. These included buprenorphines partial agonism and the associated ceiling effect with its implied limitation of analgesia. There were also difficulties in understanding of the bell-shaped doseresponse curve, and the possibility that blockade of the mu-opioid receptor by the avid binding of buprenorphine led to the inability of other opioids to bind and be effective. Non-naloxone reversibility of any respiratory depression, a marked incidence of emetic adverse events and a liability to abuse, were also considered potential problems. However, the last quarter of a century has seen the gradual emergence of a number of publications that have refuted the previous detractions.
There is no recorded evidence of a ceiling dose for analgesia in man and the facility to produce 100% pain relief has been conclusively shown in spite of a ceiling effect being present for properties of the drug other than analgesia.1 2 Doseresponse studies of buprenorphine in animals have shown data characterized by flattened or U-shaped (bell-shaped) curves, with dose-related increases of efficacy in the lower dose range but higher doses producing no greater or a decreased effect. This function has been demonstrated with many responses including analgesia, respiratory depression, gastrointestinal motility, and precipitation of withdrawal in morphine-dependent animals.3 4 However, in man, buprenorphine produces typical mu-opioid agonist effects of long duration including analgesia, euphoria, sedation, and pupillary constriction.5 Only with respiratory depression has a bell-shaped curve been shown,6 indicating a likelihood of low abuse liability and increased safety.
Persistent block of the mu-opioid receptor does not occur with buprenorphine, and subsequent use of other opioids is not affected either in acute or chronic situations.6 7 This is particularly relevant should break-through pain occur either during initial dose-titration or continued therapy in progressive disease. In such situations, the most logical agent to use would be sublingual buprenorphine, both for its speed of onset and as acute tolerance to adverse effects would have already developed. However, any other strong opioid of choice could be used but the change of molecule might well induce additional adverse effects.
Any respiratory depression produced by buprenorphine can readily be reversed by naloxone, albeit in somewhat elevated doses,8 and by other opioid antagonists,9 and the respiratory stimulant, doxapram.10 Apart from that following intraspinal administration,11 respiratory depression with buprenorphine has rarely been recorded in the world literature.12 Nausea, vomiting, and constipation have been shown to occur significantly less with buprenorphine than with morphine.1 Patients prone to emetic problems in the acute situation may be treated prophylactically with a multimodal antiemetic approach.14
The low abuse potential of buprenorphine was originally shown to be due to its molecular configuration and also, more recently, to a lack of induction of internalization of opioid receptors.13 This has been of value both in long term analgesic use and in the weaning of addicts from opioid abuse, where buprenorphine has been shown to be safe, effective, and exhibiting fewer adverse effects than other agents used in such situations.5 16 17
Irrespective of the route of administration, excretion of buprenorphine is mainly via the faeces following biliary excretion of conjugated, unchanged drug and conjugated Phase 1 metabolites. Only a small amount of drug-related material is excreted in the urine18 and, consequently, buprenorphine is the safest opioid to use in cases of renal impairment.19
The primary metabolite, N-dealkylbuprenorphine (norbuprenorphine), has a weak, mu-agonist analgesic effect after chronic dosing but is 10 times more potent than the parent compound as a respiratory depressant. This effect is reversible with naloxone and ß-flunaltrexamine, and concentrations in the lung compared with the brain suggest that the depressant effect on respiration is mediated via opioid mu-receptors in the lung rather than in the brain.20
A transdermal formulation of buprenorphine was introduced into clinical practice in 2001. This formulation utilises the favourable physicochemical properties of the drug,10 and new matrix technology. In this latter formulation, buprenorphine is intimately incorporated within an adhesive polymer matrix (acrylate vinyl acetate), allowing the constant release of active agent into the systemic circulation at a predetermined rate over a minimum period of 72 h. The dose of buprenorphine delivered is dependent upon the amount of drug held in the matrix and the area of the patch.21
Three patch strengths are available delivering 35 µg h1 (0.84 mg 24h1), 52.5 µg h1 (1.261 mg 24 h1) and 70 µg h1 (1.68 mg 24 h1), giving an analgesic plasma concentration (>100 pg ml1) after 31 h for the 35 µg h1 patch, and after 13 h for the 52.5 µg h1 and 70 µg h1 patches. Steady state plasma concentration is reached with each patch strength after three patch applications, for instance 9 days. For all three patch strengths, elimination half-time is about 25 h.22 The pharmacokinetic data are of the utmost importance when considering changing medication from buprenorphine to another opioid or vice versa. Following the establishment of plasma concentration steady state, when compared with the sublingual preparation, transdermal buprenorphine offers better quality of analgesia; the absence of peaks and troughs reduces both the incidence of adverse events and the abuse potential.21
The matrix type of patch does not suffer from the two major disadvantages of the reservoir patch, namely damage to the matrix patch does not produce dose dumping with its possible associated toxicity, and the active component is not readily available for abstraction from the patch for subsequent social abuse. In addition, patch technology improves patient compliance as the tablet load is reduced or eliminated, problems with difficulty in swallowing oral medications are alleviated, and the psychological connotation of a patch is life-style related rather than illness related as with tablets, capsules or injection medicines.23 The patch is also easy to use by both patient and carer.22
Initial clinical experience and recent data from the German Post Marketing Surveillance Study show good analgesic efficacy at all three dose levels. In addition, there is a low incidence of systemic and local adverse effects.22 Other advantages seen with buprenorphine include a cardioprotective mechanism via effective opening of ATP-sensitive potassium channels in peripheral tissue,24 a lack of the immunotoxicity seen with many of the other strong opioids including morphine,25 and maintained behavioural/cognitive function during long term therapy.26
Indications for use of transdermal buprenorphine include all chronic moderate to severe pain of cancer or non cancer-related origin likely to be sensitive to opioids,27 28 but especially neuropathic pain,29 30 and musculoskeletal problems including arthritis.31 Although sustained release preparations have only a limited value in acute pain, the ease of use and low adverse event profile make transdermal buprenorphine an attractive possibility in postoperative pain, being used as background analgesia to patient controlled analgesia (PCA) and eventually as the sole analgesic.
Has the time come for an old dog to wag its tail?
Clinical science has, over the last quarter of a century, established buprenorphine as a unique yet valuable strong opioid analgesic. The misunderstandings that have constrained its potential have been swept away, allowing the future to discover whether it has a significant role in clinical analgesia. It also indicates that we should look more carefully at the physicochemical properties of even familiar drugs, relating them to clinical application, so that optimal formulations may be achieved. The future for buprenorphine in its new formulation looks more attractive, particularly now that the misunderstandings, which dogged its early progression have been comprehensively corrected.
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