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Examination of the preclinical antinociceptive efficacy of buprenorphine and its designation as full- or partial-agonist
Abstract
The terminology used to characterize agonist action in preclinical stud-ies requires careful application based on fundamental concepts of receptor theory. Especially important in this regard are the terms 'intrinsic activity', 'efficacy' and 'full-' or 'partial-' agonist. Failure to apply or interpret these terms properly can lead to erroneous prediction or perception of a compound's clinical utility. This is illustrated here in reporting our recent antinociceptive studies with buprenor-phine. Buprenorphine has been classified in some preclinical studies as a 'partial agonist', but there is now clear evidence using PET technology that buprenorphine can produce analgesia at less than full receptor occupancy, the definition of a 'full agonist', and that its analgesic effectiveness extends to cancer and neuropathic pain. We measured buprenorphine-induced antinociceptive time-course and dose-response curves in the same test (tail-dip/flick in mice) at three stimulus intensities: 48, 55, and 65 • C. Buprenorphine antinociception was inversely related to stimulus intensity, producing 100% antinociception at 48 • C. The dose-response curve was curvilinear (bell-shaped) at each temperature. The current results demonstrate the necessity of defining threshold criteria with the use of the term 'full agonist' and, more generally, highlight the importance of careful and accurate use of, and pre-dictions based upon, the terms 'intrinsic activity', 'efficacy', and 'full-' or 'partial-' agonist.
... The terminology used to characterize agonist action in preclinical studies must be carefully applied according to the fundamental concepts of receptor theory. 10 The terms "intrinsic activity," "efficacy," and "full-" or "partial-" agonists are especially important; failure to apply or interpret these terms correctly can lead to erroneous prediction or perception of a compound's clinical utility. For example, buprenorphine has sometimes been labeled a "partial agonist" based on the results of early preclinical studies, but more recent work demonstrates that it is inappropriate to regard buprenorphine as a "partial" agonist on the basis of preclinical data, or to predict a ceiling effect in the clinical setting. ...
... For example, buprenorphine has sometimes been labeled a "partial agonist" based on the results of early preclinical studies, but more recent work demonstrates that it is inappropriate to regard buprenorphine as a "partial" agonist on the basis of preclinical data, or to predict a ceiling effect in the clinical setting. 10 Affinity characterizes the interaction between drug and receptor. Intrinsic activity involves the binding of the drug to the receptor and the production of a second messenger (G-proteins in the case of opioids). ...
... In animal models buprenorphine has been shown to produce a full analgesic effect 13 that is dependent upon the intensity of the stimulus. 10 In addition, radio-labeling studies in humans have demonstrated that full analgesia is produced at less than 100% occupancy of the m-opioid receptor 14 -the definition of a full agonist. As the presence or absence of a ceiling effect depends upon the intensity of the stimulus and the specific endpoint chosen, it is perfectly possible for one endpoint (eg, respiratory depression) to exhibit this effect, but not another (eg, analgesia). ...
Despite the increasing clinical use of transder-mal buprenorphine, questions have persisted about the possibility of a ceiling effect for analgesia, its combination with other m-opioid agonists, and the reversibility of side effects. In October 2008, a consensus group of experts met to review recent research into the pharmacology and clinical use of buprenorphine. The objective was to achieve consensus on the conclusions to be drawn from this work. It was agreed that buprenorphine clearly behaves as a full m-opioid agonist for analgesia in clinical practice, with no ceiling effect, but that there is a ceiling effect for respiratory depression, reducing the likelihood of this potentially fatal adverse event. This is entirely consistent with receptor theory. In addition, the effects of buprenorphine can be completely reversed by naloxone. No problems are encountered when switching to and from buprenorphine and other opioids, or in combining them. Buprenorphine exhibits a pronounced antihyperalgesic effect that might indicate potential advantages in the treatment of neuro-pathic pain. Other beneficial properties are the compound's favorable safety profile, particularly in elderly patients and those with renal impairment, and its lack of effect on sex hormones and the immune system. The expert group agreed that these properties, as well as proven efficacy in severe pain and favorable tolerability, mean that buprenor-phine can be considered a safe and effective option for treating chronic cancer and noncancer pain.
... The terminology used to characterize agonist action in preclinical studies must be carefully applied according to the fundamental concepts of receptor theory. 10 The terms "intrinsic activity," "efficacy," and "full-" or "partial-" agonists are especially important; failure to apply or interpret these terms correctly can lead to erroneous prediction or perception of a compound's clinical utility. For example, buprenorphine has sometimes been labeled a "partial agonist" based on the results of early preclinical studies, but more recent work demonstrates that it is inappropriate to regard buprenorphine as a "partial" agonist on the basis of preclinical data, or to predict a ceiling effect in the clinical setting. ...
... For example, buprenorphine has sometimes been labeled a "partial agonist" based on the results of early preclinical studies, but more recent work demonstrates that it is inappropriate to regard buprenorphine as a "partial" agonist on the basis of preclinical data, or to predict a ceiling effect in the clinical setting. 10 Affinity characterizes the interaction between drug and receptor. Intrinsic activity involves the binding of the drug to the receptor and the production of a second messenger (G-proteins in the case of opioids). ...
... In animal models buprenorphine has been shown to produce a full analgesic effect 13 that is dependent upon the intensity of the stimulus. 10 In addition, radio-labeling studies in humans have demonstrated that full analgesia is produced at less than 100% occupancy of the m-opioid receptor 14 -the definition of a full agonist. As the presence or absence of a ceiling effect depends upon the intensity of the stimulus and the specific endpoint chosen, it is perfectly possible for one endpoint (eg, respiratory depression) to exhibit this effect, but not another (eg, analgesia). ...
Despite the increasing clinical use of transdermal buprenorphine, questions have persisted about the possibility of a ceiling effect for analgesia, its combination with other μ-opioid agonists, and the reversibility of side effects. In October 2008, a consensus group of experts met to review recent research into the pharmacology and clinical use of buprenorphine. The objective was to achieve consensus on the conclusions to be drawn from this work. It was agreed that buprenorphine clearly behaves as a full μ-opioid agonist for analgesia in clinical practice, with no ceiling effect, but that there is a ceiling effect for respiratory depression, reducing the likelihood of this potentially fatal adverse event. This is entirely consistent with receptor theory. In addition, the effects of buprenorphine can be completely reversed by naloxone. No problems are encountered when switching to and from buprenorphine and other opioids, or in combining them. Buprenorphine exhibits a pronounced antihyperalgesic effect that might indicate potential advantages in the treatment of neuropathic pain. Other beneficial properties are the compound's favorable safety profile, particularly in elderly patients and those with renal impairment, and its lack of effect on sex hormones and the immune system. The expert group agreed that these properties, as well as proven efficacy in severe pain and favorable tolerability, mean that buprenorphine can be considered a safe and effective option for treating chronic cancer and noncancer pain.
... Such a biphasic dose-response curve ('hormesis') is actually more common than generally recognized (Calabrese, 2008). This was strikingly evident in a recent study in mouse (Raffa and Ding, 2007), which showed that the dose-effect curve reached 100% maximum possible effect, but was biphasic, increasing at doses below 10 mg/kg and decreasing at doses above 10 mg/kg. While the precise molecular mechanism responsible for the biphasic response in this test is still debated, it has been speculated that it may be due to activation of the nociceptin/orphanin-FQ (NOP; ORL1, opioid receptor like) receptor which compromises buprenorphine's antinociceptive effect (reviewed in Lewis, 1995 andBudd andRaffa, 2005). ...
... Our aim here was to apply a novel approach to answer this question. Toward that end we here analyze data on mouse tail immersion from Raffa and Ding (2007), as well as new data (Cowan, unpublished results) in the rat, in a calculation that uses the concept of dose equivalence, the same principle that underlies additivity in isobolographic analysis. ...
... The tail immersion/flick test data in mice reported in Raffa and Ding (2007) were used in the analysis. Briefly stated, the mice were placed into restraining holders and the distal portion of their tail was lowered into a temperature-controlled water bath (48 °C). ...
Buprenorphine, like many other drugs, displays a biphasic dose-response relation ('hormesis'), viz., its antinociceptive effect in some preclinical models increases up to some dose level (often achieving 100% effect) and decreases at high-doses. A decreasing component was evident in the tail-flick tests described here, occurring in both the mouse and the rat. While the mechanism of dose-related decline in antinociceptive effect, when observed, might be related to nociceptin/orphanin-FQ, the precise mechanism remains unknown. Regardless of the mechanism, the values of this dose-related decline yield data that can be used to calculate the dose-effect relation of the decreasing (unknown second) component. The calculation, which uses the same concept of dose equivalence that underlies additivity in isobolographic analysis, was employed here from tail-flick data obtained in mouse and rat. The derived dose-effect curves of the second component, though differing in efficacy between mouse and rat, displayed a very notable similarity. This novel technique offers possible insight into the dual low-dose (analgesic), high-dose (addiction medication) uses of buprenorphine.
... It is an analogue of the poppy-derived opiate alkaloid thebaine and possesses high binding affinity for opioid receptors (Villiger and Taylor, 1981; Rothman et al., 1995; Huang et al., 2001; Lutfy and Cowan, 2004), including those in situ in human brain (Greenwald et al., 2003). Buprenorphine shares some of the general preclinical (Cowan, 1995) and clinical attributes of standard opioid agonists such as morphine and fentanyl (see Budd and Raffa, 2005), but differs by having slow receptor dissociation kinetics, a biphasic ('bell'-or 'inverted U'-shaped) dose–response relation in a few animal models (see Christoph et al., 2005); clinical implications discussed in Raffa and Ding, 2007) and a ceiling effect on respiratory depression, but not analgesia, in humans (Dahan et al., 2006). It has been suggested that morphine and buprenorphine induce anti-nociception through different transduction mechanisms (Aceto and Cowan, 1991). ...
... All three of the drugs attained 100% anti-nociception. At time of peak effect [determined in previous work (Raffa and Ding, 2007)], the order of potency was fentanyl (ED 50 = 0.0011 0.0003 mg·kg -1 ) > buprenorphine (ED50 = 0.21 0.04 mg·kg -1 ) > morphine (ED50 = 0.55 0.11 mg·kg -1 ). The ED50 of buprenorphine was again comparable to previous values [e.g. ...
... Pretreatment (10 min) with naloxone (10 mg·kg -1 i.p.) had no significant effect alone in the 48°C water-immersion tail-flick A BFigure 1 Anti-nociceptive dose–response curves for buprenorphine (Bup), morphine (M) and fentanyl (F) in the (A) abdominal constriction and (B) warm water (48°C) tail-dip/flick test (Raffa and Ding, 2007) in mice (mean SEM). Baseline latency = 7.6 0.6 (Bup), 6.7 0.7 (M) and 7.3 0.4 (F) s. n = 4–8 mice per group. ...
Buprenorphine displays attributes of opioids, but also some features distinct from them. We examined spinal and supraspinal signal transduction of buprenorphine-induced anti-nociception in mice compared with morphine and fentanyl.
The opioid receptor antagonist naloxone, Pertussis toxin (PTX), G(z) protein antisense and nociceptin/orphanin-FQ receptor agonist nociceptin, and antagonist, JTC-801, were injected supraspinally (intracerebroventricular) and spinally (intrathecal). Also the cell-permeable Ser/Thr protein phosphatase inhibitor okadaic acid was given supraspinally.
Spinal naloxone (20 microg) or PTX (1 microg) attenuated morphine, fentanyl and buprenorphine (s.c.) anti-nociception. Supraspinal naloxone or PTX attenuated morphine and fentanyl, but not buprenorphine anti-nociception. Spinal G(z) protein antisense did not alter buprenorphine, morphine or fentanyl anti-nociception and supraspinal G(z)-antisense did not alter morphine or fentanyl anti-nociception. However, supraspinal G(z)-antisense (not random sense) reduced buprenorphine anti-nociception. Peripheral JTC-801 (1 mgxkg(-1), i.p.) enhanced the ascending (3 mgxkg(-1)) and descending (30 mgxkg(-1)) portions of buprenorphine's dose-response curve, but only spinal, not supraspinal, nociceptin (10 nmolxL(-1)) enhanced buprenorphine anti-nociception. Intracereboventricular okadaic acid (0.001-10 pg) produced a biphasic low-dose attenuation, high-dose enhancement of buprenorphine(3 or 30 mgxkg(-1), s.c.) anti-nociception, but did not affect morphine or fentanyl anti-nociception.
Buprenorphine has an opioid component to its supraspinal mechanism of analgesic action. Our present results reveal an additional supraspinal component insensitive to naloxone, PTX and nociceptin/orphanin-FQ, but involving G(z) protein and Ser/Thr protein phosphatase. These data might help explain the unique preclinical and clinical profiles of buprenorphine.
... 21 Buprenorphine demonstrates different intrinsic activities as a partial agonist at μ-opioid receptors and at ORL1 receptors, an antagonist at κ-receptors, and an agonist at δ-opioid receptors in vitro. 9,22,23 The analgesic effects of buprenorphine appear to derive largely (if not solely) from its actions at the μ-opioid receptor, 24 while the contributions of actions at the other opioid receptors are unclear. 9 The slow dissociation of buprenorphine from μ-opioid receptors may contribute to its long duration of activity. ...
... [6][7][8]17,23,25,[32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] Although buprenorphine is considered a partial agonist at the μ-opioid receptor in vitro and an antagonist at the κ-opioid receptor, studies have shown that buprenorphine can be expected to produce pharmacological effects similar to those of full μ-agonists, especially at the comparatively lower buprenorphine doses delivered by the BTDS. 9,7,22,25 It has been reported that buprenorphine behaves like a full μ-opioid agonist at analgesic doses, and the partial agonistic property, high affinity binding, or slow dissociation of buprenorphine does not have a negative effect on the availability of μ-opioid receptors or on its interaction with full μ-opioid agonists. 23,25 In animals pretreated with an analgesic dose of buprenorphine, the addition of morphine, oxycodone, or hydromorphone results in an additive or synergistic effect. ...
Background
The buprenorphine transdermal system (BTDS) is approved in the US for the management of chronic pain. Due to its high affinity for μ-opioid receptors with a slow dissociation profile, buprenorphine may potentially displace or prevent the binding of competing μ-opioid-receptor agonists, including immediate-release (IR) opioids, in a dose-dependent manner. Health care professionals may assume that the use of IR opioids for supplemental analgesia during BTDS therapy is not acceptable.
Materials and methods
This post hoc analysis evaluated the use of IR opioids as supplemental analgesia during the management of moderate–severe chronic pain with BTDS at 52 US sites (BUP3015S, NCT01125917). Patients were categorized into IR-opioid and no-IR-opioid groups. At each visit of the extension phase, adverse events, concomitant medications, and information from the Brief Pain Inventory (BPI) were recorded.
Results
The most common supplemental IR opioids prescribed during BTDS treatment (n=354) were hydrocodone–acetaminophen and oxycodone–acetaminophen. The mean daily dose of IR opioids (morphine equivalents) for supplemental analgesia was 22 mg. At baseline, BPI – pain intensity and BPI – interference scores were higher for patients in the IR-opioid group. In both treatment groups, scores improved by week 4, and then were maintained throughout 6 months of the open-label extension trial. The incidence of treatment-emergent adverse events was similar in both groups.
Conclusion
Patients who were prescribed IR opioids reported lower scores for BPI pain intensity and pain interference to levels similar to patients receiving BTDS without IR opioids, without increasing the rate or severity of treatment-emergent adverse events. Patients prescribed concomitant use of IR opioids with BTDS had greater treatment persistence. The results of this post hoc analysis provide support for the concomitant use of IR opioids for supplemental analgesia during the management of moderate–severe chronic pain with BTDS.
... The action of opioid drugs on these receptors activates G-proteins, which leads to a reduction in transmission of nerve impulses and inhibition of neurotransmitter release. 1 Buprenorphine is a slow-onset, long-acting, µ-opioid receptor agonist. 2 However, there is not a consensus about buprenorphine' s action on κ-opioid receptors. [3][4][5][6][7] The current consensus in human medi-cine is that buprenorphine has full µ-opioid receptor agonistic activity [8][9][10] and that its analgesic effect is dose dependent. 10 Investigators of an early study 11 of buprenorphine described a plateau or ceiling effect whereby increased dosages would not result in improved analgesia or a bell-shaped dose-response curve in which higher dosages would have a lower analgesic effect. ...
... [3][4][5][6][7] The current consensus in human medi-cine is that buprenorphine has full µ-opioid receptor agonistic activity [8][9][10] and that its analgesic effect is dose dependent. 10 Investigators of an early study 11 of buprenorphine described a plateau or ceiling effect whereby increased dosages would not result in improved analgesia or a bell-shaped dose-response curve in which higher dosages would have a lower analgesic effect. Results of studies conducted since then and reevaluation of data have revealed that the concept of a ceiling effect may have been a misinterpretation of results 12 and that there is only a ceiling effect for respiratory depression. ...
Objective:
To evaluate the thermal antinociceptive effects and duration of action of buprenorphine hydrochloride after IM administration to American kestrels (Falco sparverius).
Animals:
12 healthy 3-year-old American kestrels.
Procedures:
Buprenorphine hydrochloride (0.1, 0.3, and 0.6 mg/kg) and a control treatment (saline [0.9% NaCl] solution) were administered IM in a randomized crossover experimental design. Foot withdrawal response to a thermal stimulus was determined 1 hour before (baseline) and 1.5, 3, and 6 hours after treatment administration. Agitation-sedation scores were determined 3 to 5 minutes before each thermal stimulus. Adverse effects were monitored for 6 hours after treatment administration.
Results:
Buprenorphine hydrochloride at 0.1, 0.3, and 0.6 mg/kg, IM, increased thermal threshold for 6 hours, compared with the response for the control treatment. There were no significant differences among buprenorphine treatments. A mild sedative effect was detected at a dose of 0.6 mg of buprenorphine/kg.
Conclusion and clinical relevance:
At the doses tested, buprenorphine hydrochloride resulted in thermal antinociception in American kestrels for at least 6 hours, which suggested that buprenorphine has analgesic effects in this species. Further studies with longer evaluation periods and additional forms of noxious stimuli, formulations, dosages, and routes of administration are needed to fully evaluate the analgesic effects of buprenorphine in American kestrels.
... For example, some in vitro studies have also classified morphine as a partial m-opioid receptor agonist [20]. In addition, antinociceptive dose-response curves for buprenorphine [21] and morphine [22][23][24] The history of buprenorphine. Buprenorphine was originally developed as an analgesic and was subsequently used for OUD before novel delivery systems allowed for approval in chronic pain management [8,9,12,13]. ...
Objective:
An expert panel convened to reach a consensus on common misconceptions surrounding buprenorphine, a Schedule III partial µ-opioid receptor agonist indicated for chronic pain. The panel also provided clinical recommendations on the appropriate use of buprenorphine and conversion strategies for switching to buprenorphine from a full µ-opioid receptor agonist for chronic pain management.
Methods:
The consensus panel met on March 25, 2019, to discuss relevant literature and provide recommendations on interpreting buprenorphine as a partial µ-opioid receptor agonist, prescribing buprenorphine before some Schedule II, III, or IV options, perioperative/trauma management of patients taking buprenorphine, and converting patients from a full µ-opioid receptor agonist to buprenorphine.
Results:
The panel recommended that buprenorphine's classification as a partial µ-opioid receptor agonist not be clinically translated to mean partial analgesic efficacy. The panel also recommended that buprenorphine be considered before some Schedule II, III, or IV opioids in patients with a favorable risk/benefit profile on the basis of metabolic factors, abuse potential, and tolerability and that buprenorphine be continued during the perioperative/trauma period. In addition, switching patients from a full µ-opioid receptor agonist to buprenorphine should be considered with no weaning period at starting doses that are based on the previous opioid dose.
Conclusions:
These recommendations provide a framework for clinicians to address most clinical scenarios regarding buprenorphine use. The overall consensus of the panel was that buprenorphine is a unique Schedule III opioid with favorable pharmacologic properties and a safety profile that may be desirable for chronic pain management.
... Buprenorphine is a potent semisynthetic highly lipophilic opioid analgesic that is largely used in the multimodal treatment of acute pain. The drug has a complex pharmacologic profile but is generally considered as a partial mu opioid agonist [3,4]. Buprenorphine causes negligible cardiovascular effects and it is used for the treatment of mild to moderate pain such as ovariohysterectomy (OVH) in dogs and cats because of its long-lasting analgesic properties and few adverse-effects [4][5][6]. ...
Abstract Background Buprenorphine is a potent lipophilic opioid analgesic that is largely used in the multimodal treatment of acute pain. Simbadol (buprenorphine hydrochloride) is the first and only FDA-approved high-concentration formulation of buprenorphine for use in cats. The aim of this study was to evaluate the analgesic efficacy of carprofen in combination with one of two commercial formulations of buprenorphine (Simbadol and Vetergesic, 1.8 mg/mL and 0.3 mg/mL, respectively) in dogs undergoing ovariohysterectomy. Twenty-four dogs were included in a randomized, prospective, controlled, clinical trial. Patients were randomly divided into 2 groups as follows. Dogs were premedicated with acepromazine (0.02 mg/kg) and either 0.02 mg/kg of Vetergesic or Simbadol intramuscularly (Vetergesic group – VG; Simbadol group – SG, respectively; n = 12/group). General anesthesia was induced with propofol and maintained with isoflurane in 100% oxygen. Carprofen (4.4 mg/kg SC) was administered after induction of anesthesia. Heart rate, respiratory rate, blood pressure, pulse oximetry, pain scores using the Glasgow Composite Pain Scale Short Form (CMPS-SF), sedation scores using a dynamic interactive visual analogue scale and adverse events were evaluated before and after ovariohysterectomy by an observer who was unaware of treatment administration. If CMPS-SF scores were ≥ 5/20, dogs were administered rescue analgesia (morphine 0.5 mg/kg IM). Statistical analysis was performed using linear mixed models and Fisher’s exact test (p
... Buprenorphine has been described as a "partial agonist" in pharmacological terms, but that may be misleading in that it does not act as a "partial agonist" in terms of analgesia [39,40]. Its dosing range for analgesic effect is 0.2 -7 mg. ...
... Buprenorphine is a partial agonist at mu-opioid and at ORL-1 (nociceptin) receptors, an antagonist at kappa opioid receptors, and an agonist at delta opioid receptors [1][2][3]. Buprenorphine is available in different formulations for example intravenous, sublingual, buccal, and transdermal formulations. ...
Objectives: To study the effect of transdermal buprenorphine on QTc prolongation at dose levels of 10, 40, and 80 mcg/h, (BTDS 10, BTDS 40, BTDS 80).
Methods: Two randomized, placebo- and positive-controlled, parallel-group, dose-escalating clinical studies evaluated healthy adult subjects randomized to BTDS, placebo, or moxifloxacin in the first study; and to BTDS only, BTDS plus naltrexone, naltrexone alone at the same dose, placebo, or moxifloxacin in the second study. QT intervals were corrected for heart rate using data from each individual subject (QTcI).
Results: In the first study (n=44), the maximum upper bounds of the 90% confidence interval (CI) for mean placebo-corrected change from baseline in QTcI across 13 time points over 24 hours were: 10.0 msec for BTDS 10 (Day 6) and 13.3 msec for BTDS 40 (Day 13); and 17.0 msec (Day 6) and 15.5 msec (Day 13) for moxifloxacin, respectively.
Similarly, in the second study (n=66), the upper bound of the 90% CI for mean placebo-corrected change from baseline for QTcI was under 10 msec at all time points for BTDS 10 (maximum upper bound, 5.63 msec), over 10 msec at 5 time points for BTDS 40 (maximum 11.81 msec) and over 10 msec at all 13 time points for BTDS 80 (maximum, 14.14 msec). Naltrexone administered with BTDS eliminated the QTcI prolongation seen with supratherapeutic BTDS doses (BTDS 40, BTDS 80) administered without naltrexone.
Conclusions: At the therapeutic dose of 10 mcg/h, BTDS has no clinically significant effect on QTc. At supratherapeutic doses of 40 and 80 mcg/h, BTDS treatment produces prolongation of QTcI similar in magnitude to that produced by a 400 mg dose of moxifloxacin. Despite the modest, dose-dependent increase in QTcI noted in these studies, transdermal buprenorphine has not been associated with proarrhythmic effects.
... 24 This terminology -a partial agonist -can be misleading, in that buprenorphine often acts like a full agonist in terms of clinical analgesic effect. 34 It offers durable analgesia in that it has high affinity for binding to MOR and slow dissociation from the MOR in the central nervous system. 35 Unlike other opioids, buprenorphine has been associated with antihyperalgesia 36 and has a ceiling effect for both gastrointestinal side effects and respiratory depression. ...
Joseph V Pergolizzi Jr,1 Robert B Raffa,2,3 Charles Fleischer,1 Gianpietro Zampogna,1 Robert Taylor Jr1 1NEMA Research, Naples, FL, 2University of Arizona College of Pharmacy, Tucson, AZ, 3Temple University School of Pharmacy, Philadelphia, PA, USA Abstract: With a global prevalence of ~9%–12%, low back pain (LBP) is a serious public health issue, associated with high costs for treatment and lost productivity. Chronic LBP (cLBP) involves central sensitization, a neuropathic pain component, and may induce maladaptive coping strategies and depression. Treating cLBP is challenging, and current treatment options are not fully satisfactory. A new BioErodible MucoAdhesive (BEMA®) delivery system for buprenorphine has been developed to treat cLBP. The buccal buprenorphine (BBUP) film developed for this product (Belbuca™) allows for rapid delivery and titration over a greater range of doses than was previously available with transdermal buprenorphine systems. In clinical studies, BBUP was shown to effectively reduce pain associated with cLBP at 12 weeks with good tolerability. The most frequently reported side effects with the use of BBUP were nausea, constipation, and vomiting. There was no significant effect on the QT interval vs placebo. Chronic pain patients using other opioids can be successfully rotated to BBUP without risk of withdrawal symptoms or inadequate analgesia. The role of BBUP in managing cLBP remains to be determined, but it appears to be a promising new product in the analgesic arsenal in general. Keywords: buccal, transmucosal, buprenorphine, chronic low back pain, BEMA, drug delivery Belbuca
... e., no ceiling effect) in animal models of pain, irrespective of the intensity and type of the pain stimulus [24]. On the other hand, a ceiling effect was observed regarding opioid related side effects including limited respiratory depression, leading to an improved safety profile when compared to fentanyl [25,26]. The antinociceptive dose range in rodents is ≤ 0.1 mg/kg i.p. [24]. ...
Buprenorphine and the mixed agonists/antagonists nalbuphine and pentazocine, formerly classified as µ-opioid (MOP) receptor antagonists, have more recently been shown to be partial to full agonists of the human MOP receptor. These receptors do not necessarily have to be maximally activated for a full physiological response. Partial agonists can also sufficiently stimulate signaling processes leading to a full analgesic response, as shown by the effectiveness of buprenorphine, nalbuphine and pentazocine in animal pain models and in clinical settings where these drugs induce analgesia with full efficacy without a ceiling effect. Submaximal doses of MOP receptor analgesics combined with submaximal doses of buprenorphine, pentazocine, or nalbuphine result in additive to over-additive antinociceptive effects in animal experiments. Only when doses are given that exceed the therapeutic dose range may the antinociceptive effect be reduced to the effect of either opioid alone. The analgesic effects of pentazocine and nalbuphine combined with morphine are reported to be additive or over-additive in various clinical pain conditions. Buprenorphine, which clinically behaves as a full MOP receptor agonist for pain relief, can be combined with full opioid agonists without precipitating withdrawal. Thus, the overall evidence on the analgesic effects of buprenorphine, pentazocine or nalbuphine combined with opioid analgesics under various clinical pain conditions contradicts the consensus that these compounds diminish MOP receptor analgesia when co-administered with a full MOP receptor agonist.
© Georg Thieme Verlag KG Stuttgart · New York.
... 45,76,79 Additional benefits of buprenorphine include a ceiling effect on respiratory depression and a lack of immunosuppression at doses relevant for analgesia. 30,57,61 Side effects in rats are usually limited but include sedation, cardiovascular depression, decreased appetite, and gastrointestinal distress, which may or may not be accompanied by pica. 15,19,63 Administration of buprenorphine by the oral route in rats is limited by a lack of information regarding its pharmacokinetics and conflicting reports of its efficacy. ...
Effective pain management for rats and mice is crucial due to the continuing increase in the use of these species in biomedical research. Here we used a recently validated operant orofacial pain assay to determine dose-response curves for buprenorphine and tramadol when mixed in nut paste and administered to male and female rats. Statistically significant analgesic doses of tramadol in nut paste included doses of 20, 30, and 40 mg/kg for female rats but only 40 mg/kg for male rats. For male rats receiving buprenorphine mixed in nut paste, a significant analgesic response was observed at 0.5 and 0.6 mg/kg. None of the doses tested produced a significant analgesic response in female rats. Our results indicate that at the doses tested, tramadol and buprenorphine produced an analgesic response in male rats. In female rats, tramadol shows a higher analgesic effect than buprenorphine. The analgesic effects observed 60 min after administration of the statistically significant oral doses of both drugs were similar to the analgesic effects of 0.03 mg/kg subcutaneous buprenorphine 30 min after administration. The method of voluntary ingestion could be effective, is easy to use, and would minimize stress to the rats during the immediate postoperative period.
... Among the opioid agents, buprenorphine may be described as having a unique pharmacology [10] . Although often described as a partial agonist based on in vitro data,this term is misleading, because buprenorphine exerts a full analgesic effect in most preclinical studies [13,14] andin humans, radio-labeling studies demonstrate that full analgesia can be produced with less than 100% occupancy of the µ-opioid receptor, which is the definition of a full agonist [15] . This is likely due to the contribution of other analgesic mechanisms [8,16] . ...
Chronic non-cancer pain is prevalent in Mexico and its pharmacologic treatment requires clinicians to balance the risks and benefits of various analgesic agents. NSAIDs and paracetamol (acetaminophen) can be effective for mild to moderate pain, but safety considerations place limitations on their use. Opioids are safe and effective, but have opioid-associated side effects plus the potential for abuse. Against this background, it is important to appraise other options with regard to favorable efficacy and safety – such aslow-dose transdermal buprenorphine. Buprenorphine, both in transdermal and oral formulations, has been available in Mexico for a number of years yet just recently a Low-Dose Transdermal Patch formulation has been available for the management chronic non-cancer pain of moderate intensity in adults. Buprenorphine is an opioid agent with a unique pharmacological profile, such that it has a ceiling effect for respiratory depression, but no ceiling effect for analgesia. It can be used without dose adjustment in the elderly and in patients with impaired kidney function (unique among opioids). Its small lipophilic molecule makes it well suited to transdermal formulations, which offer steadystate round-the-clock analgesia after three days with clinical convenience and easier patient compliance. Buprenorphine is an effective analgesic in chronic non-cancer pain patients, and its good tolerability and lower abuse potential may make lowdose transdermal buprenorphine appropriate for a broad range of patients.
... Trabajos más recientes han demostrado que no es adecuado caracterizar a la buprenorfina como agonista "parcial" en base a datos preclínicos o inferir un efecto techo en el contexto clínico (26,30). En varios modelos animales la buprenorfina ha demostrado producir un efecto agonista puro (31) que depende de la intensidad del estímulo (32). Estudios radio-marcados en humanos han demostrado que se Náuseas, vómitos obtiene analgesia total con menos del 100% de ocupación de receptores opioides mu (33), por eso se comporta como agonista puro. ...
Background: Pain is one of the most feared outcomes of surgery by patients, yet current practices of pain management are suboptimal. Failure to address acute postoperative pain can have a variety of consequences that affect physical and psychological aspects of the patient. Current perioperative pain management normally consists of opioid therapy, which has been a mainstay for many years. However, use of opioids can have moderate risks, including nausea/vomiting, dizziness, and constipation, or more severe risks, including respiratory depression and immunosupression. Aim: In order to address some of the issues surrounding perioperative pain management, a group of key opinion leaders gathered at an international summit to analyze the current practices of perioperative pain management. One of the topics focused on buprenorphine's role in perioperative pain and the information discussed is presented throughout this article. Conclusion: Buprenorphine has been demonstrated to be effective and safe in many postoperative pain models. Its administration versatility, its manageable side effects, and its use in combination with other analgesics allow buprenorphine therapy to be successful in perioperative pain management.
... Buprenorphine is a semisynthetic opioid that has been termed a partial m-opioid receptor agonist and a partial k-receptor antagonist. 23,24 Dissociation from the opioid receptors proceeds slowly, resulting in a prolonged duration of action and a relatively prolonged and weak withdrawal. Buprenorphine is available in multiple formulations (oral, sublingual, parenteral); our proceedings focused on the transdermal or patch delivery system. ...
Pain is a global epidemic, exacerbated by barriers to access of opioid analgesics. Regulations about opioids attempt to protect public health from the risks of harmful use of opioids, diversion, and dependence. Transdermal buprenorphine is an effective opioid analgesic agent with unique properties that may make it particularly well suited for more widespread use. It is a versatile analgesic product with demonstrated safety and effectiveness in cancer and noncancer pain populations. Its pharmacological properties make it a first-line opioid analgesic for geriatric patients and patients with renal dysfunction; no dosing adjustments need to be made. The 7-day transdermal delivery system is convenient for patients and promotes compliance. A low dose of buprenorphine can provide effective and well-tolerated pain relief. Although buprenorphine has been associated with certain opioid-related adverse effects, such as dizziness and nausea, it is associated with a lower rate of constipation than many other opioid analgesics. The potential for nonmedical use of buprenorphine is relatively low compared with other opioid agents. Buprenorphine has a relatively low likeability for nonmedical use and the transdermal matrix patch renders the substance particularly difficult to extract for illicit purposes.
Copyright © 2015. Published by Elsevier B.V.
... The fact that buprenorphine appears to be a true partial agonist on the endpoint of respiratory depression, with a ceiling effect, 42,44 cannot be generalized to analgesia, because the ability to be a partial agonist on one endpoint and a full agonist on another endpoint is mechanistically possible and easily explained. 45 Perhaps the answer lies in the multimechanistic pharmacology of buprenorphine. Its overall analgesic action is likely mediated by a combination of receptors. ...
What is known and objective:
Based on in vitro assays and select animal models, buprenorphine is commonly called a 'partial agonist'. An implication is that it should produce less analgesic effect in humans than so-called 'full agonists' such as morphine or fentanyl. However, buprenorphine has a multimechanistic pharmacology, and thus partial agonism at a specific receptor is not particularly relevant to its overall analgesic action. We review published clinical trials that directly compared the magnitude of buprenorphine's analgesic effect to analgesics commonly considered full agonists.
Comment:
Due to different signal transduction pathways, a drug can be a full agonist on one endpoint and a partial agonist on another. Therefore, we limited the present review to buprenorphine's analgesic effect.
What is new and conclusion:
Twenty-four controlled clinical trials were identified, plus a case report and dose-response curve. Based on complete or comparable pain relief, in buprenorphine had full clinical analgesic efficacy in 25 of the 26 studies.
... 7,9,10 This terminology is confusing, however, because it depends on the criteria used to define a "full" or "partial agonist" in research studies and should not be used solely for predicting efficacy of the drug. 11 Because of its pharmacodynamic (PD) profile, which exhibits a slow biophase equilibration and receptor binding, 5 buprenorphine is considered to have a delayed onset of action and long-acting analgesic properties that exert moderate analgesia with few adverse effects. 10,12 The dosage of buprenorphine commonly has been restricted as a result of early antinociceptive studies using animal models demonstrating a notorious bellshaped dose-response curve, where higher dosages led to a decreased effect or produced no analgesia. ...
Pain management is a crucial component of feline medicine and surgery. This review critically evaluates studies using buprenorphine in cats and highlights the clinical application of the opioid in this species. The pharmacokinetic-pharmacodynamic (PK-PD) modeling of IV buprenorphine has been best described by a combined effect compartmental/receptor association-dissociation model with negative hysteresis. Therefore, plasma concentrations of the drug are not correlated with analgesia, and clinicians should not expect to observe pain relief immediately after drug administration. In addition, a ceiling effect has not been demonstrated after administration of clinical doses of buprenorphine in cats; dosages of up to 0.04 mg/kg have been reported. The route of administration influences the onset, duration, and magnitude of antinociception and analgesia when using this drug in cats. At clinical dosages, the SC route of administration does not appear to provide adequate antinociception and analgesia whereas the buccal route has produced inconsistent results. Intravenous or IM administration at a dosage of 0.02–0.04 mg/kg is the preferred for treatment of pain in the acute setting. A literature search found 14 clinical trials evaluating buprenorphine sedation, analgesia, or both in cats. There were 22 original research studies reporting the antinociceptive effects of buprenorphine by means of thermal threshold, mechanical threshold, or both, minimal alveolar concentration, or PK-PD. Individual variability in response to buprenorphine administration has been reported, indicating that buprenorphine may not provide sufficient analgesia in some cats. Pain assessment is important when evaluating the efficacy of buprenorphine and determining whether additional analgesic treatment is needed.
... Studies have demonstrated that tail-flick tests provide dose and temperature-sensitive responses to buprenorphine in mice. [23] However and perhaps because the method seems intuitive, there is scarce detail in published reports describing mouse restraint procedures. Light restraint using a towel has been reported. ...
The change in the reaction time of a tail or paw exposed to a thermal stimulus is a measure of nociceptive activity in laboratory animals. Tail-flick and plantar thermal sensitivity (Hargreaves) tests are non-invasive, minimize stress, and can be used to screen animals for phenotype and drug activity.
Hargreaves testing has been widely used in rats. We investigated its use to measure the activity of opiate analgesia in mice.
Mice were used in thermal stimulus studies at 1-5 hours and 1-5 days to test acute and extended release preparations of buprenorphine.
Hargreaves testing had limited value at 1-5 hours because mice can have an obtunded response to opiate therapy. Tail-flick studies with restrained mice are not affected by the initial locomotor stimulation.
The present report describes a simple restraint system for mice. The utility of the system is demonstrated by examining the efficacy of acute and extended release buprenorphine injections in Balb/c and Swiss mice.
Standardized tail-flick testing provides a sensitive robust method to monitor opiate activity in mice.
Opiates have a long history of medical use as effective analgesics associated with well‐described side effects, including euphoria, respiratory depression, constipation, bradycardia, and histamine release, among others. The search for opiate analogs that retain effective analgesic qualities without detrimental side effects has yielded numerous compounds, including buprenorphine. Early studies of buprenorphine demonstrated analgesic effectiveness with a favorable safety profile, leading to the approval of formulations for use in humans. Since then, advances in receptor theory and molecular cloning of opioid receptors have led to a deeper understanding of buprenorphine pharmacology. More recent studies of receptor affinity and intrinsic activity have shown that buprenorphine is a μ‐ and κ‐opioid receptor agonist, a nociceptin orphanin peptide agonist, and a δ‐opioid receptor antagonist. Buprenorphine appears to have a primary spinal analgesic mechanism with complex supraspinal actions. It is considered a full agonist for pain but a partial agonist for other clinical endpoints such as respiratory depression. In feline medicine, buprenorphine is approved as low‐ and high‐concentration injectable solutions, in addition to the most recently introduced long‐acting transdermal formulation. Several investigational and compounded formulations have also been evaluated. There are contrasting differentiable features that include pharmacokinetics, onsets‐ and durations‐of‐action, routes of administration, and formulation constituents. Available buprenorphine formulations allow clinicians to select a formulation based on the anticipated duration of pain associated with various surgical procedures, and to provide interventions as needed. In light of the newly approved transdermal buprenorphine solution in cats and progress in buprenorphine pharmacology, the objective of this review is to examine the history and pharmacology of buprenorphine relative to full opioid agonists, where appropriate, integrating these insights into advances within feline medicine.
OBJECTIVE To evaluate thermal antinociceptive effects and pharmacokinetics of buprenorphine hydrochloride after IM administration to cockatiels ( Nymphicus hollandicus ).
ANIMALS 16 adult (≥ 2 years old) cockatiels (8 males and 8 females).
PROCEDURES Buprenorphine hydrochloride (0.3 mg/mL) at each of 3 doses (0.6, 1.2, and 1.8 mg/kg) and saline (0.9% NaCl) solution (control treatment) were administered IM to birds in a randomized within-subject complete crossover study. Foot withdrawal response to a thermal stimulus was determined before (baseline) and 0.5, 1.5, 3, and 6 hours after treatment administration. Agitation-sedation scores were also determined. For the pharmacokinetic analysis, buprenorphine (0.6 mg/kg) was administered IM to 12 of the birds, and blood samples were collected at 9 time points ranging from 5 minutes to 9 hours after drug administration. Samples were analyzed with liquid chromatography–mass spectrometry. Pharmacokinetic parameters were calculated with commercial software.
RESULTS Buprenorphine at 0.6, 1.2, and 1.8 mg/kg did not significantly change the thermal foot withdrawal response, compared with the response for the control treatment. No significant change in agitation-sedation scores was detected between all doses of buprenorphine and the control treatment. Plasma buprenorphine concentrations were > 1 ng/mL in all 4 birds evaluated at 9 hours.
CONCLUSIONS AND CLINICAL RELEVANCE Buprenorphine at the doses evaluated did not significantly change the thermal nociceptive threshold for cockatiels or cause sedative or agitative effects. Additional studies with other pain assessments and drug doses are needed to evaluate the analgesic and adverse effects of buprenorphine in cockatiels and other avian species.
Buprenorphine is an opiate used for pain management and to treat opiate addiction. The cytokine leptin can modulate nociception, but the extent to which buprenorphine-induced antinociception varies as a function of leptin signaling has not been characterized. Four congenic mouse lines with phenotypes that include differences in body weight and leptin status were used to test the hypothesis that the antinociceptive effects of buprenorphine vary as function of sex and leptin signaling. Each mouse line was comprised of males (n=12) and females (n=12) for a total of 96 animals. Groups included C57BL/6J (B6) mice (wild type), B6 mice with diet-induced obesity (DIO), obese B6.Cg-Lep(ob)/J (ob/ob) mice lacking leptin, and obese B6.BKS(D)-Lepr(db)/J (db/db) mice with dysfunctional leptin receptors. The dependent measure was tail flick latency (TFL) in seconds for mouse-initiated tail removal from a warm water bath. Independent variables were intraperitoneal administration of saline (control) or buprenorphine (0.3mg/kg). Within every mouse line, buprenorphine significantly increased TFL relative to saline. Compared to the other mouse lines, db/db mice with dysfunctional leptin receptors had a significantly longer TFL after saline and after buprenorphine. TFL did not vary significantly by body weight or sex. The results provide novel support for the interpretation that acute thermal nociception is associated with altered leptin signaling.
This chapter describes some properties of commonly used sedative, anesthetic, and analgesic agents for laboratory animals. Inhalants (mainly isoflurane and sevoflurane) are becoming increasingly popular in laboratory animal anesthesia for a number of reasons. Chloral hydrate is used occasionally in rodent anesthesia for neuropharmacology studies. Tribromoethanol is used primarily in mice although its popularity has declined markedly because of undesirable side-effects. Despite growing emphasis on animal welfare and refinement of animal models, less than 25% of laboratory rodents undergoing surgical procedure are given analgesic drugs. Non-steroidal anti-inflammatory drugs (NSAIDs) are the second most commonly administered agents for pain relief in rodents and other laboratory animal species. Despite their abundant use in animal models of chronic pain, very few studies have looked at the benefit of gabapentin and pregabalin in laboratory animals as part of postsurgical pain management. Finally, the chapter discusses laboratory rodents and lagomorphs, and non-human primates.
Buprenorphine HCl (BUP) is a μ-opioid agonist used in laboratory rodents. New formulations of buprenorphine (for example, sustained-released buprenorphine [BUP SR], extended-release buprenorphine [BUP ER]) have been developed to extend the analgesic duration. In a crossover design, 8 adult rats were injected subcutaneously with either BUP, BUP SR, BUP ER, or saline, after which voluntary running-wheel activity, arterial blood gases, and thermal withdrawal latency were assessed. Wheel running was decreased at 24 h compared with baseline in all treatment groups but returned to baseline by 48 h. Arterial pH, HCO3⁻, and CO2 were not changed between groups or over time. However, arterial oxygen was lower than baseline in the BUP (-8 ± 2 mm Hg), BUP SR (-7 ± 1 mm Hg), and BUP ER (-17 ± 2 mm Hg) groups compared with saline controls (3 ± 2 mm Hg); the BUP ER group showed the greatest decrease when all time points were combined. BUP increased the withdrawal latency at 1 h (15% ± 3%), whereas BUP ER increased latencies at 4, 8, 12, and 48 h (35% ± 11%, 21% ± 7%, 26% ± 7%, and 22% ± 9%, respectively) and BUP SR prolonged latencies at 24, 48, and 72 h (15% ± 6%, 18% ± 5%, and 20% ± 8%, respectively). The duration of thermal analgesia varied between buprenorphine formulations, but all 3 formulations reduced voluntary-running activity at 24 h after injection and might cause hypoxemia in normal adult rats. © Copyright 2016 by the American Association for Laboratory Animal Science.
Increase in the number of opioid dependent pregnant women delivering babies at risk for neonatal abstinence syndrome (NAS) prompted a General Accountability Office (GAO) report documenting deficits in research and provider knowledge about care of the maternal/fetal unit and the neonate. There are three general sources of dependence: untreated opioid use disorder (OUD), pain management, and medication assisted treatment with methadone or buprenorphine.
The aim of this study was to determine the effect of pretreatment with hydromorphone or buprenorphine on thermal antinociception induced by fentanyl in cats.
Seven healthy cats received five different treatments consisting of two drugs. Drug one was administered intravenously 1 h before drug two. Drug two was given as an intravenous loading dose followed by an infusion for 4 h. The drug combinations used were: buprenorphine 20 µg/kg followed by fentanyl (BF; 7 μg/kg, 7 μg/kg/h), buprenorphine 20 µg/kg followed by 0.9% saline solution (B), hydromorphone 0.07 mg/kg followed by 0.9% saline solution (H), hydromorphone 0.07 mg/kg followed by fentanyl (HF; 7 μg/kg, 7 μg/kg/h) and 0.9% saline solution followed by fentanyl (F; 7 μg/kg, 7 μg/kg/h). Thermal thresholds were obtained prior to treatment and at predetermined times up to 7 h after drug one.
Thermal thresholds were significantly higher than baseline in all treatment groups as follows: H from 0.25 to 2.50 h; B from 0.25 to 2.50 h; F from 1.25 to 5.50 h; HF from 0.25 to 5.50 h and BF from 0.25 to 5.25 h. Thermal thresholds were significantly higher in HF and BF than in F treatment before the fentanyl infusion was commenced (from 0.25 to 1.00 h). During the fentanyl infusion thermal thresholds in BF compared with F were lower at 1.75 h and from 2.50 to 3.50 h. After the constant rate infusion of fentanyl was started, thermal thresholds were significantly lower in HF compared with F at one time point (3 h).
Pretreatment with buprenorphine did partially inhibit the antinociceptive action of fentanyl. Hydromorphone did inhibit the antinociceptive action of fentanyl at one single time point in cats.
© The Author(s) 2015.
To evaluate the tolerability, sedative and analgesic effects of methadone in combination with medetomidine for premedication prior to neutering in healthy cats.
This was an assessor-blinded, randomised, clinical research study. Forty-five cats were recruited and divided into three treatment groups of 15. Following premedication with medetomidine (20 µg/kg) and one of the three test drugs - methadone 0.5 mg/kg, buprenorphine 20 µg/kg or butorphanol 0.4 mg/kg intramuscularly - anaesthesia was induced with propofol and maintained with isoflurane, and neutering was carried out. Sedation and physiological parameters were assessed before premedication, after premedication before induction of anaesthesia, and at 90 mins and 2, 3, 4, 6, 7, 8 and 24 h after premedication. Pain and mechanical nociceptive threshold were assessed at similar time points.
There were no differences between groups with respect to age, sex, duration of anaesthesia or surgery. Most cats had low pain scores in the postoperative period, with small differences in pain scores between groups at individual time points only. Five, two and no cats required additional rescue analgesia in the postoperative period in the butorphanol, methadone and buprenorphine groups, respectively, and was not significantly different between groups.
Medetomidine combined with methadone for premedication prior to neutering in healthy cats provided adequate analgesia for the first 6 h after administration with no adverse effects; effects overall were comparable with medetomidine combined with buprenorphine or butorphanol. Administration of further analgesia with methadone at 6 h and a non-steroidal anti-inflammatory drug at 8 h provided adequate analgesia for the first 24 h after surgery.
© ISFM and AAFP 2014.
A prospective, randomised, blinded, clinical trial in 47 ponies compared butorphanol and buprenorphine administered intravenously with detomidine prior to castration under anaesthesia. Detomidine 12 μg/kg intravenously was followed by butorphanol 25 μg/kg (BUT) or buprenorphine 5 μg/kg (BUP) before induction of anaesthesia with intravenous ketamine and diazepam. Quality of sedation, induction and recovery from anaesthesia, response to tactile stimulation, and surgical conditions were scored. If anaesthesia was inadequate 'rescue' was given with intravenous ketamine (maximum three doses) followed by intravenous thiopental and detomidine. Time from induction to first rescue, total ketamine dose and number of rescues were recorded. Postoperative locomotor activity was scored and abnormal behaviour noted. Simple descriptive scales were used for all scoring. Data were analysed using two-way analysis of variance, t tests, Mann-Whitney or Fisher's exact tests as appropriate; P<0.05 was considered statistically significant. Cryptorchid animals did not undergo surgery, but castration was successfully completed in 18 BUT and 20 BUP. More incremental ketamine (P=0.0310) and more rescue drugs (P=0.0165) were required in BUT and more postoperative locomotor activity occurred in BUP (P=0.0001). There were no other differences between groups. Both opioids were suitable for premedication prior to castration but buprenorphine appeared to provide better intraoperative analgesia.
Background:
The history of discovery of analgesic drugs has followed a trajectory from original serendipitous discovery of plant-derived substances to laboratory creation of customized molecules that are intentionally designed to interact with specific receptors of neurotransmitters involved in either the transmission of the pain signal or the attenuation of such a signal. The drugs most recently developed have been designed to provide incremental greater separation between pain relief and adverse effects. The result has been drugs that have individualized pharmacodynamic and pharmacokinetic characteristics that represent specific advances in basic science and translate into unique clinical profiles. Several of the drugs include non-opioid components. They retain some of the features of opioids, but have distinct clinical characteristics that differentiate them from traditional opioids. Thus they defy simple classification as opioids.
Scope:
A summary is provided of the development of the modern view of multi-mechanistic pain and its treatment using analgesics that have multi-mechanisms of action (consisting of both opioid and non-opioid components). Descriptions of examples of such current analgesics and of those that have pharmacokinetic characteristics that result in atypical opioid clinical profiles are given.
Findings:
By serendipity or design, several current strong analgesics have opioid components of action, but have an additional non-opioid mechanism of action or some pharmacokinetic feature that gives them an atypical opioid clinical profile and renders them not easily classified as classical opioids.
Conclusion:
An appreciation that there are now opioid analgesics that differentiate from classical opioids in ways that defy their simplistic classification as opioids suggests that recognition of subclasses of opioid analgesics would be more accurate scientifically and would be more informative for healthcare providers and regulators. This would likely lead to positive outcomes for the clinical use and regulatory control of the current drugs, and provide direction/strategy for the discovery of new drugs.
To determine whether methadone, administered before orthopaedic surgery, results in improved postoperative analgesia compared to buprenorphine.
Thirty-eight dogs undergoing orthopaedic surgeries (the majority being tibial tuberosity advancement or elbow arthrotomy) were premedicated with 0 · 03 mg/kg acepromazine and either 20 µg/kg buprenorphine or 0 · 5 mg/kg methadone, intramuscularly, allocated randomly. Anaesthesia was induced with propofol intravenously to effect and maintained with isoflurane in oxygen. 0 · 2 mg/kg meloxicam was administered at anaesthetic induction. Sedation was assessed by means of a dynamic interactive visual analogue and simple descriptive scales and pain by dynamic interactive visual analogue and the short form Glasgow composite pain scales, by a single observer blinded to treatment group at intervals for 8 hours following premedication.
Sedation scores were higher than baseline in both groups following premedication until the end of the assessment period (P = 0 · 0001), with no differences between groups. Pain scores were lower overall in dogs premedicated with methadone (dynamic interactive visual analogue scale P = 0 · 048; short form Glasgow composite pain scale P = 0 · 0045), and these dogs required less additional analgesia (42%, compared to 79% premedicated with buprenorphine, P = 0 · 045).
At the doses investigated, methadone produced superior analgesia to buprenorphine for 8 hours postoperatively in dogs undergoing orthopaedic surgery.
Regulatory climate, medical culture, and history have created geographic distinctions in analgesics. In particular, Europe has experience with many commercially available analgesics that have recently been introduced or may soon be introduced to the USA market. The authors selected 4 analgesics widely used in Europe that may be less familiar to American clinicians: transdermal buprenorphine, essential oxygen oil, tapentadol ER, and intravenous diclofenac. These agents are far from the only such agents worthy of consideration but were selected as they range from a new formulation for a familiar drug, an over-the-counter topical product, an oral opioid, and a very popular nonsteroidal anti-inflammatory agent. The clinical studies performed on these agents can help inform physician prescribing choices, when these drugs are available in the USA.
Buprenorphine is a long-acting opiate with a high therapeutic index. The authors review the pharmacology, toxicity, analgesic effects and delivery of buprenorphine for use in laboratory mice and rats. Buprenorphine-based analgesic therapy has a substantial record of safety, and there is growing evidence of its effectiveness for treating post-operative pain. Nonetheless, more research is needed to determine optimal delivery systems and analgesic regimens for pain therapy in laboratory animals.
Context:
Transdermal formulations of buprenorphine offer controlled delivery of buprenorphine for sustained analgesic efficacy with reduced adverse events (AEs) compared with the other modes of administration. A buprenorphine transdermal system (BTDS) delivering 5, 10, or 20 mcg/hour for seven days is now marketed in the U.S. as Butrans(®) (Lohmann Therapie-System AG, Andernach Germany), a Schedule III single-entity opioid analgesic indicated for the management of moderate and chronic pain in patients requiring continuous around-the-clock analgesia for an extended period.
Objectives:
This was a randomized open-label study in healthy subjects to characterize the steady-state buprenorphine pharmacokinetics after the delivery of three consecutive seven-day BTDS applications.
Methods:
Thirty-seven subjects were randomized to receive three consecutive BTDS 10 mcg/hour (BTDS 10) patches applied to the deltoid or upper back for seven days each. Blood samples for buprenorphine concentration measurements were taken. Safety was assessed using recorded AEs, clinical laboratory test results, vital signs, pulse oximetry, physical examinations, and electrocardiograms. Patch adhesion assessments were taken.
Results:
Analysis of Cmin demonstrated that steady state was reached during the first BTDS 10 application. No significant difference in Cmin was observed across the three applications. Total and peak plasma buprenorphine exposures were similar after each of the seven-day administrations of BTDS.
Conclusion:
Three consecutive once-weekly applications of BTDS 10 provided consistent and sustained delivery of buprenorphine. Steady-state plasma concentrations were reached within 48 hours of the first application of BTDS 10. Patch adhesion analysis confirmed the appropriateness of the seven-day application period. Overall, BTDS 10 was safe and well tolerated.
Comparison of the analgesic effect of buprenorphine at 20 or 40 μg kg(-1) .
An investigator 'blinded', randomised study.
Twenty six dogs presented for ovariohysterectomy.
Dogs were premedicated intramuscularly with acepromazine 0.03 mg kg(-1) and buprenorphine at either 20 (B20, n = 12) or 40 μg kg(-1) (B40, n = 14) followed by anaesthetic induction with propofol and maintenance with isoflurane. During anaesthesia non invasive blood pressure, heart rate, respiratory rate, blood oxygen saturation, inspired and expired volatile agent, end-tidal carbon dioxide and ECG were recorded. Pain and sedation were assessed using interactive VAS scores; mechanical nociceptive thresholds were measured at the wound and hindlimb--all were assessed before and up to 22 hours after administration. Carprofen was used for rescue analgesia.
There were no significant differences between the two groups for any of the parameters examined. Rescue analgesia was required around 5 hours after administration of buprenorphine in a significant number of animals. Sedation was good preoperatively and scores decreased over time postoperatively. Hock thresholds did not change over time; wound thresholds decreased significantly compared to the baseline value from 3 hours onwards.
Administration of buprenorphine at either 20 or 40 μg kg(-1) IM with acepromazine provided good pre-operative sedation. Cardiovascular and respiratory values remained within clinically acceptable limits during anaesthesia. There was no evidence that increasing dose increased adverse events that may be associated with opioid administration (e.g. bradycardia and respiratory depression).
Increasing the dose of buprenorphine from 20 to 40 μg kg(-1) did not provide any benefits with respect to analgesia after ovariohysterectomy as assessed using the VAS scoring system.
To investigate the antinociceptive effects of buprenorphine administered in combination with acepromazine in horses and to establish an effective dose for use in a clinical environment.
To evaluate the responses to thermal and mechanical stimulation following administration of 3 doses of buprenorphine compared to positive (butorphanol) and negative (glucose) controls.
Observer blinded, randomised, crossover design using 6 Thoroughbred geldings (3-10 years, 500-560 kg). Thermal and mechanical nociceptive thresholds were measured 3 times at 15 min intervals. Horses then received acepromazine 0.05 mg/kg bwt with one of 5 treatments i.v.: 5% glucose (Glu), butorphanol 100 µg/kg bwt (But) buprenorphine 5 µg/kg bwt (Bup5), buprenorphine 7.5 µg/kg bwt (Bup7.5) and buprenorphine 10 µg/kg bwt (Bup10). Thresholds were measured 15, 30, 45, 60, 90, 120, 150, 180, 230 min, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 24 h post treatment administration. The 95% confidence intervals for threshold temperature (ΔT) for each horse were calculated and an antinociceptive effect defined as ΔT, which was higher than the upper limit of the confidence interval. Duration of thermal antinociception was analysed using a within-subjects ANOVA and peak mechanical thresholds with a general linear model with post hoc Tukey tests. Significance was set at P<0.05.
Mean (± s.d.) durations of thermal antinociception following treatment administration were: Glu 0.5 (1.1), But 2.9 (2.0), Bup5 7.4 (2.3), Bup7.5 7.8 (2.7) and Bup10 9.4 (1.1) h. B5, B7.5 and B10 were significantly different from Glu and But. No serious adverse effects occurred, although determination of mechanical thresholds was confounded by locomotor stimulation.
Administration of acepromazine and all doses of buprenorphine produced antinociception to a thermal stimulus for significantly longer than acepromazine and either butorphanol or glucose. Potential relevance: This study suggests that buprenorphine has considerable potential as an analgesic in horses and should be examined further under clinical conditions and by investigation of the pharmacokinetic/pharmacodynamic profile.
In addition to analgesia opioids may also enhance pain sensitivity. Opioid-induced hyperalgesia, typically associated with potent mu-opioid agonists (e.g. fentanyl, morphine, and heroin), may be of clinical importance due to the possible counteraction of analgesia and/or paradoxical enhancement of a pre-existing pain condition during opioid therapy. Buprenorphine, a potent opioid analgesic, has a complex pharmacology on mu and kappa receptors. Buprenorphine has a better analgesia/toxicity profile (a ceiling effect for respiratory depression, less potential for abuse) compared to typical mu-opioids. Little is known about buprenorphine-induced hyperalgesia. Potentially, a lack of hyperalgesia with these other characteristics could make buprenorphine a more desirable opioid for management of chronic pain. Responsiveness to high and ultra-low doses of buprenorphine was examined following acute and repeated administration in a rat model of thermal nociception (the tail-flick test). Buprenorphine produced a dose-related antinociception. Loss of efficacy (tolerance) followed by enhanced pain sensitivity occurred with repeated dosing of buprenorphine. Delayed hyperalgesia, seen in association with antinociceptive tolerance, was blocked by the NMDA receptor antagonist, ketamine. Buprenorphine (ultra-low dose) resulted in immediate hyperalgesia, which was also reversed by ketamine, in a dose-related fashion. No tolerance to hyperalgesia was seen with repeated dosing of low-dose buprenorphine. The antinociceptive effect of buprenorphine was diminished in rats, which previously exhibited hyperalgesia with buprenorphine. In summary, bimodal properties of buprenoprhine were separately demonstrated: pronociceptive at ultra-low dose and antinociceptive at higher doses. An NMDA-receptor mechanism was involved in hyperalgesia with buprenorphine.
To assess the effects of premedication with buprenorphine on the characteristics of anaesthesia induced with ketamine/medetomidine.
Prospective crossover laboratory study.
Six female New Zealand White rabbits.
Rabbits received, on occasions separated by 7 days, either buprenorphine (0.03 mg kg(-1)) or saline subcutaneously (SC) as premedication, followed 1 hour later by SC ketamine (15 mg kg(-1)) and medetomidine (0.25 mg kg(-1)) (K/M). At pre-determined time points reflex responses and cardiopulmonary parameters were recorded and arterial blood samples taken for analysis. Total sleep time was the duration of loss of the righting reflex. Duration of surgical anaesthesia was the time of suppression of the ear pinch and pedal withdrawal reflexes. Wilcoxon signed-ranks tests were used to compare data before (T(0)) and 10 minutes after (T(10)) injection with K/M.
All animals lost all three reflex responses within 10 minutes of injection of K/M. The duration of loss of these reflexes significantly increased in animals that received buprenorphine. At induction, animals that had received buprenorphine tended to have a lower respiration rate but there were no significant differences in arterial PCO(2), PO(2) or pH between treatments. Hypoxaemia [median PaO(2) < 6.0 kPa (45 mmHg)] developed in both treatments at T(10) but there was no significant difference between treatments. Mean arterial pressure (MAP) was lower at T(10) in animals that had received buprenorphine.
Premedication with buprenorphine significantly increased the duration of anaesthesia induced by K/M, with no significant depression of respiration further to the control treatment within the first 10 minutes of anaesthesia. The MAP decreased but this was not reflected in a difference in other physiological parameters. These data show that premedication with buprenorphine, before K/M anaesthesia in the rabbit, has few negative effects and may provide beneficial analgesia.
One hundred and fifty-three cats undergoing surgery in seven veterinary practices in Great Britain were studied. They were randomly allocated to receive either 10-20 microg/kg buprenorphine or 0.4 mg/kg butorphanol with acepromazine before anaesthesia with propofol, Saffan or thiopentone and isoflurane or halothane. Routine monitoring was undertaken. Pain and sedation were assessed blind using a four point (0-3) simple descriptive scale (SDS) at 1, 2, 4, 8 and 24h. Pain and sedation data were compared using non-parametric statistical tests and continuous data using t tests or analysis of variance (ANOVA). Anaesthesia and surgery were uneventful, and cardiorespiratory data were within normal limits. After surgery, overall, more cats had pain score 0 after buprenorphine and more had pain score 3 after butorphanol (P=0.0465). At individual time points, more cats had lower pain scores after buprenorphine at 2 (P=0.040) and 24 (P=0.036)h. At 24h 83% after buprenorphine and 63% after butorphanol had pain score 0 (P<0.04). Buprenorphine provided better and longer lasting postoperative analgesia than butorphanol.
Buprenorphine is a promising drug for the treatment of chronic pain and opioid dependence. The aim of the present work was to evaluate the feasibility of lipid nanoparticles with different oil/fatty ester ratios for injection of buprenorphine. To improve the release properties and analgesic duration of the drug, ester prodrugs were also incorporated into the nanoparticles for evaluation. Linseed oil and cetyl palmitate were respectively chosen as the liquid lipid and solid lipid in the inner phase of the nanoparticulate systems. Differential scanning calorimetry (DSC) was performed, and the particle size, zeta potential, molecular environment, and lipid/water partitioning were determined to characterize the state of the drug/prodrug and lipid modification. The in vitro release kinetics were measured by a Franz assembly. DSC showed that systems without oil (solid lipid nanoparticles, SLNs) had a more ordered crystalline lattice in the inner matrix compared to those with oil (nanostructured lipid carriers, NLCs and lipid emulsion, LE). The mean diameter of the nanoparticles ranged between 180 and 200nm. The in vitro drug/prodrug release occurred in a delayed manner in decreasing order as follows: SLN>NLC>LE. It was found that the release rate was reduced following an increase in alkyl ester chains in the prodrugs. The in vivo antinociception was examined by a cold ethanol tail-flick test in rats. Compared to an aqueous solution, a prolonged analgesic duration was detected after an intravenous injection of buprenorphine-loaded SLNs and buprenorphine propionate (Bu-C3)-loaded NLCs (with 10% linseed oil in the lipid phase). The Bu-C3 in NLCs even showed a maximum antinociceptive activity for 10h. In vitro erythrocyte hemolysis and lactate dehydrogenase (LDH) release from neutrophils demonstrated a negligible toxicity of these carriers. Our results indicate the feasibility of using lipid nanoparticles, especially SLNs and NLCs, as parenteral delivery systems for buprenorphine and its prodrugs.
The semi-synthetic opioid, buprenorphine, has the general structure of morphine but differs from it in significant ways, both pharmacologically and clinically. A number of long-term studies have shown effective, long-lasting analgesia in moderate to severe cancer and non-cancer pain, including neuropathic pain, with a low incidence of constipation, nausea, dizziness and tiredness. The treatment of moderate to severe chronic pain has improved as a result of the development of new methods of administration of this substance, particularly the introduction of the transdermal drug delivery system, which offers a number of advantages over the usual oral and parenteral routes.
A panel of experts specialising in palliative care and pain treatment was convened in November 2007 to discuss their clinical experiences with transdermal buprenorphine and other analgesics. The aim was to provide practical guidance on the treatment of cancer pain with transdermal buprenorphine, particularly when there is a need for increasing pain relief leading to high and increasing doses. A literature search on the use of transdermal buprenorphine was carried out for the panel meeting (based on a search of PubMed to November 2007 - since updated by an additional search for the period to February 2009) and a number of case histories were presented and discussed. This commentary article presents this evidence and the consensus findings of the expert panel.
The Panel reached consensus that transdermal buprenorphine was a valuable treatment for chronic cancer pain, including its neuropathic components. A number of general recommendations were made. Large-scale, randomised clinical studies are needed to provide product comparisons on the use of analgesics in the treatment of neuropathic pain although it was recognised that such studies may not be practicable. Data on the treatment of acute and chronic pain should be kept separate in general. Physicians should be made more aware of the problem of hyperalgesic effects of some opioids in long term use. Buprenorphine in contrast has been described to exert an antihyperalgesic effect. The development of analgesic tolerance with some opioids in long term use and the lack of it with buprenorphine requires further studies. The registered dose range of 35-140 microg/h was considered adequate to achieve sufficient pain relief in most patients although some members of the panel presented data showing that increases beyond this dose range provided improved pain relief if slow titration is used. However, it was generally felt that more evidence was needed before this could become generally acceptable.
The consensus was that transdermal buprenorphine has a valuable role to play in the treatment of chronic cancer pain because of its efficacy and good safety and tolerability profile, including a low risk of respiratory depression, a lack of immunosuppression and a lack of accumulation in patients with impaired renal function.
This study evaluated thermal threshold (TT) testing for investigation into NSAID analgesia in cats. Seven cats participated in two crossover studies. TTs were measured on thoracic skin using a device developed specifically for cats. Skin temperature was recorded, then the heater activated. At the behavioural end point heating was stopped and temperature (=TT) recorded. In part 1, TTs were measured following subcutaneous (SC) ketoprofen or saline. In part 2, the process was repeated after intradermal kaolin induced mild inflammation at the test site. TTs were measured before treatment and two hourly for 24 h. In part 1, skin temperature did not change but in part 2 it increased more after saline than ketoprofen. TT did not change significantly after any treatment. However, after ketoprofen TT fell below the 95% confidence interval (CI) in part 1 and increased above it in part 2. The method detected some NSAID effects but is unlikely to be sufficiently sensitive for study of NSAID analgesia.
Ongoing interest in the improvement of pain management with opioid analgesics had led to the investigation of sublingual opioid absorption. The present report determined the percent absorption of selected opioid analgesics from the oral cavity of normal subjects under conditions of controlled pH and swallowing when a 1.0 ml aliquot of the test drug was placed under the tongue for a 10-minute period. Compared with morphine sulfate at pH 6.5 (18% absorption), buprenorphine (55%), fentanyl (51%), and methadone (34%) were absorbed to a significantly greater extent (p less than 0.05), whereas levorphanol, hydromorphone, oxycodone, heroin, and the opioid antagonist naloxone were not. Overall, lipophilic drugs were better absorbed than were hydrophilic drugs. Plasma morphine concentration-time profiles indicate that the apparent sublingual bioavailability of morphine is only 9.0% +/- 11.9% (SD) of that after intramuscular administration. In the same subjects the estimated sublingual absorption was 22.4% +/- 9.2% (SD), indicating that the sublingual absorption method may overestimate apparent bioavailability. When the oral cavity was buffered to pH 8.5, methadone absorption was increased to 75%. Thus, an alkaline pH microenvironment that favors the unionized fraction of opioids increased sublingual drug absorption. Although absorption was found to be independent of drug concentration, it was contact time dependent for methadone and fentanyl but not for buprenorphine. These results indicate that although the sublingual absorption and apparent sublingual bioavailability of morphine are poor, the sublingual absorption of methadone, fentanyl, and buprenorphine under controlled conditions is relatively high.
In order to use buprenorphine as an analgesic in immunological experiments, we have studied the potential immunotoxicity of buprenorphine. Three-week-old male Wistar Riv: TOX rats were subcutaneously treated with buprenorphine by injection of 0.1, 0.4, or 1.6 mg/kg body weight per day over a period of 4 weeks. Concentrations used were within the range for analgesia in rats. A slight decrease of body weight gain was observed at the highest dose in one but not in a duplicate study. Decreased liver weights were observed in all dose groups. Histopathologically glycogen storage was decreased and fatty vacuolation was found to be increased starting from the lowest dose group. The relative but not absolute weight of the lungs was slightly increased at the lowest dose, this phenomenon was therefore not dose-dependent. Histopathologically, a dose-dependent increase in interstitial pneumonia in the lung was found. At the 2 higher dose levels the weight of the adrenal glands was increased. No haematological changes were found, nor were there effects on bone marrow.
In one of 2 studies indications of potential immunotoxicity noted were: an increased weight of the thymus, as well as an increased weight of popliteal and mesenteric lymph nodes. No effects on the weight of the spleen were found. Histologically, there were no changes in the lymphoid organs tested. Total immunoglobulin A concentrations in serum were significantly decreased in the highest dose group, whereas IgG concentrations were increased, albeit not statistically significantly. IgM and IgE concentrations showed no alterations.
Two types of immune function assays were carried out: determination of natural killer cell activity and of mitogen responsiveness of spleen cells. Whereas natural killer activity was unaffected, increased responses to concanavalin-A, phytohaemagglutinin, pokeweed mitogen as well as lipopolysaccharide were found, although never statistically significant.
The results indicate that buprenorphine may have a slight stimulatory influence on the immune system at dose levels that are used for analgesia. The effects on the immune system that were noted were modest. Moreover, they were observed in conjunction with other toxicological effects, and can therefore either be direct or indirect.
The purpose of this study was to characterize the acute effects of buprenorphine, an opioid partial mu-agonist, across a wide range of doses in comparison to methadone.
Healthy adult male volunteers, who had experience with but were not physically dependent on opioids, participated while residing on a closed research unit. Four subjects received buprenorphine (0, 1, 2, 4, 8, 16, and 32 mg sublingually and five subjects received methadone (0, 15, 30, 45, and 60 mg orally) in ascending order at 1-week intervals. Physiologic, subjective, and behavioral measures were monitored for 96 hours after drug administration.
Both drugs produced typical opioid agonist effects (positive mood, sedation, respiratory depression, and miosis), some of which persisted for 24 to 48 hours. A plateau was observed for the dose effects of buprenorphine on subjective measures and respiratory depression. Pharmacokinetic data revealed that plasma concentrations of buprenorphine were linearly related to dose, indicating no limits on sublingual absorption in this dose range.
This study shows a plateau on buprenorphine effects, consistent with its partial agonist classification, and that single doses of buprenorphine up to 70 times the recommended analgesic dose are well tolerated by nondependent humans.
Cell Surface Receptors: A Short Course on Theory and Methods, 3rd Edition, links theoretical insights into drug-receptor interactions described in mathematical models with the experimental strategies to characterize the biological receptor of interest. The study of receptors has changed considerably over the period of the publication of the three editions of this book. The cloning of several genomes makes it unlikely that preparations of receptors now or in the future will arise from their purification as trace proteins from native tissues, but rather from a myriad of molecular approaches. Nonetheless, understanding the molecular mechanisms and ultimately the in vivo biology of these receptors means that investigators will engage in molecular, cellular and ultimate in vivo strategies. It should be of value to investigators who want to identify, characterize and understand the biology of a receptor of interest. This book is primarily targeted to researchers and graduate students in the fields of molecular pharmacology, receptors, receptor biology, and signal transduction. These courses are variously found in pharmacology, molecular and cell biology, biochemistry and neuroscience. Researchers in the pharmaceutical industry working on bringing new drugs to market will also find this book useful. © 2005 Springer Science+Business Media, Inc. All rights reserved.
Background: Opioid detoxification in a primary care setting followed by ongoing substance abuse treatment may be appropriate for selected opioid-dependent patients. Objective: To compare three pharmacologic protocols for opioid detoxification in a primary care setting. Design: Randomized, double-blind clinical trial with random assignment to treatment protocols. Setting: A free-standing primary care clinic affiliated with drug treatment programs. Patients: 162 heroin-dependent patients. Interventions: Three detoxification protocols: clonidine, combined clonidine and naltrexone, and buprenorphine. Measurements: Successful detoxification (that is, when study participants received a full opioid-blocking dose [50 mg] of naltrexone), treatment retention (8 days), and withdrawal symptoms. Results: Overall, 65% of participants (36 of 55) who received clonidine, 81% (44 of 54) who received combined clonidine and naltrexone, and 81% (43 of 53) who received buprenorphine were successfully detoxified. Retention did not differ significantly across the groups: 65% of participants (36 of 55) who received clonidine, 54% (29 of 54) who received combined clonidine and naltrexone, and 60% (32 of 53) who received buprenorphine. Participants who received buprenorphine had a significantly lower mean withdrawal symptom score than those who received clonidine or combined clonidine and naltrexone. Conclusions: Participants in the combined clonidine and naltrexone group and those in the buprenorphine group were more likely to complete detoxification, although retention at 8 days did not differ among the groups. Participants who were assigned to the buprenorphine group experienced less severe withdrawal symptoms than those assigned to the other two groups.
Synopsis: Buprenorphine1, a derivative of the morphine alkaloid thebaine, is a strong analgesic with marked narcotic antagonist activity. In studies in relatively small groups of postoperative patients with moderate to severe pain, one or a few doses of buprenorphine parenterally (by intramuscular or slow intravenous injection) or sublingually2 were at least as effective as standard doses of other strong analgesics such as morphine, pethidine or pentazocine, and buprenorphine was longer acting than these agents. Only a small number of patients with chronic pain have received repeated doses, but in such patients there was no need for increased doses during several weeks to months of treatment. Buprenorphine appears to produce side effects which are similar to those seen with other morphine- like compounds, including respiratory depression. There is apparently no completely reliable specific antagonist for buprenorphine’s respiratory depressant effect, since even very high doses of the antagonist drug naloxone may produce only a partial reversal. The respiratory stimulant drug doxapram has overcome respiratory depression in volunteers and in a few patients in a clinical setting, but such studies have not been done in an overdose situation. Animal studies and a direct addiction study in a few volunteers suggest that the dependence liability of buprenorphine may be lower than that of other older morphine- like drugs. However, a slowly emerging abstinence syndrome did occur on withdrawal after very high doses administered for 1 to 2 months. A definitive statement on the drug’s dependence liability and abuse potential cannot be made until it has had much wider use for a longer period of time. In most in vitro and in vivo animal studies buprenorphine has also shown the ability to antagonise the effects of single doses of morphine, and to precipitate abstinence in animals dependent on morphine. Although in several such tests a ‘ceiling effect’ of antagonist activity occurred with higher doses not producing an increased response, in others (precipitation of abstinence in morphine dependent monkeys) such an effect was not observed. In man, the narcotic antagonist activity of buprenorphine has been demonstrated through precipitation of abstinence in narcotic dependent subjects and by reversal of fentanyl anaesthesia. The respiratory depressant activity of single equianalgesic doses of buprenorphine and morphine appears to be similar. Although a ‘ceiling effect’ for buprenorphine induced respiratory depression has been demonstrated in animals, it is presently unclear whether or not this occurs in man, but within the therapeutic dose range respiratory depression is dose related. The onset of peak respiratory depressant effect is slower after intramuscular buprenorphine than after morphine (3 hours versus 1 hour) and the duration of such an effect, although not clearly determined, is longer. In therapeutic trials published to date respiratory depression with buprenorphine has not been a problem, but such studies have usually involved single doses in fit patients undergoing surgery. The respiratory depressant effects in ‘poor risk’ patients or following repeated doses need further study. There appears to be no completely reliable specific antagonist for buprenorphine induced respiratory depression, since even very high doses of naloxone may produce only partial reversal. However, the respiratory stimulant drug doxapram has reversed respiratory depression due to buprenorphine in a few healthy volunteers and in a few patients in a clinical setting. Haemodynamic changes in healthy volunteers after intramuscular (0.15 to 0.6mg), sublingual (0.4 or 0.8mg) or oral (1 to 4mg) doses of buprenorphine have been limited to a dose related reduction in heart rate (up to 25%) and a small decrease in systolic blood pressure (about 10%), as occurred with morphine. Similar dose related effects occurred in anaesthetised patients undergoing surgery and in a few patients with myocardial infarctions, although in the latter group the heart rate remained relatively unchanged. In animal distribution studies the liver and brain contained the highest levels of radioactivity. In pregnant rats, radioactivity readily reached the placenta after oral or parenteral doses. In man, N-dealkylbuprenorphine and conjugates of this and the parent drug are the only metabolites so far identified. The pharmacological activity of these metabolites has not been studied. Excretion occurred primarily in the faeces (71% and 68% of radioactivity after 15μg/kg orally and 2μg/kg intravenously, respectively) which contained mainly unchanged buprenorphine, while urinary excretion products (15% and 27% of radioactivity after oral and intramuscular administration) were conjugates of buprenorphine and N-dealkylbuprenorphine. In a small number of patients with chronic pain, usually due to cancer, sublingual buprenorphine (up to 0.8mg 4-hourly) provided adequate pain relief for periods of up to several months but side effects (usually nausea or vomiting) required discontinuing treatment in about 1/3 to 1/2 of the ambulant patients treated in this way. Following analgesic anaesthesia, usually with fentanyl, in about 180 patients buprenorphine (usually 0.4 to 0.8mg intravenously) has been used to reverse some of the anaesthetic effects while producing continued analgesia which lasted about 8 to 12 hours after a single dose. The antagonist activity, however, was frequently more short lived, declining rapidly after 90 to 120 minutes; and a second dose of buprenorphine was often required at this time to prevent re-emergence of anaesthetic effects. Moderate to marked drowsiness has been reported in about 40 to 45 % of patients (up to 75% in some studies), but all such patients were easily arousable on stimulation. Nausea and/or vomiting occurred in about 15% of patients. Other minor side effects typical of strong analgesics such as dizziness, sweating, headache, or confusion have been reported with a widely varying incidence. Euphoria has been reported on rare occasions. Respiratory depression, as determined by laboratory measurements of respiratory function, does occur with buprenorphine, the extent of such depression being similar to that seen with other opioid drugs administered in usual clinical doses; but this has not been a problem in clinical studies to date which were usually conducted in fit patients. The effect of buprenorphine on respiration in ‘poor risk’ patients such as those with respiratory disease or congestive heart failure has not been determined. However, it appears that buprenorphine would have the same potential problems as morphine in this patient group. Administration of buprenorphine to patients already receiving large doses of narcotic drugs should be undertaken with caution until the response is established, since its antagonist activity could conceivably precipitate abstinence in this situation.
We examined the effects of several opioids that vary in intrinsic efficacy at the [micro sign]-opioid receptor alone and in combination with morphine in a rat warm water tail withdrawal procedure using 50[degree sign]C and 52[degree sign]C water (i.e., low- and high-stimulus intensities). Morphine, levorphanol, dezocine, and buprenorphine produced dose-dependent increases in antinociception using both stimulus intensities. Butorphanol produced maximal levels of antinociception at the low, but not at the high, stimulus intensity, whereas nalbuphine failed to produce antinociception at either stimulus intensity. For cases in which butorphanol and nalbuphine failed to produce antinociception alone, these opioids dose-dependently antagonized the effects of morphine. When levorphanol, dezocine, and buprenorphine were combined with morphine, there was a dose-dependent enhancement of morphine's effects. Similar effects were obtained at the low-stimulus intensity when butorphanol was administered with morphine. In most cases, the effects of these combinations could be predicted by summating the effects of the drugs when administered alone. These results indicate that the level of antinociception produced by an opioid is dependent on the intrinsic efficacy of the drug and the stimulus intensity. Furthermore, the level of antinociception produced by the opioid, not necessarily the opioids' intrinsic efficacy, determines the type of interaction among opioids. Implications: Compared with high-efficacy opioids, lower efficacy opioids produce lower levels of pain relief, especially in situations of moderate to severe pain. When opioids are given in combination, the effects can only be predicted on the basis of the antinociception obtained when the drugs are administered alone. (Anesth Analg 1999;88:407-13)
Recent studies indicate that morphine is more potent as an antinociceptive agent in male than female rodents and monkeys.
To evaluate the influence of sex, nociceptive stimulus intensity and an opioid's relative efficacy on opioid-induced antinociception in rat strains (F344 and Lewis) that display differential sensitivity to morphine antinociception.
Antinociceptive testing was conducted using a rat warm-water (50-56 degrees C) tail-withdrawal procedure. Dose-response and time-course determinations were performed with various opioids.
Across the nociceptive stimulus intensities tested, the high-efficacy mu opioids morphine, etorphine, and levorphanol were equally effective in males and females, but on average 2.5-fold more potent in males. At moderate stimulus intensities, the low-efficacy mu opioid buprenorphine was approximately 0.4-fold more potent in males, and at higher stimulus intensities more potent and effective (greater maximal effect) in males. At low stimulus intensities, the low-efficacy mu opioid dezocine and the mu/kappa opioid butorphanol were greater than 8.9-fold more potent in males, and at moderate stimulus intensities were more potent and effective in males. At a low stimulus intensity, the mu/kappa opioid nalbuphine was more potent and effective in males. At stimulus intensities in which buprenorphine, dezocine, butorphanol, and nalbuphine produced maximal effects in males but not females, these opioids antagonized the effects of morphine in females. Genotype-related differences were noted as opioids were generally more potent in F344 than Lewis males, whereas no consistent differences were observed between F344 and Lewis females.
That sex differences in the potency and effectiveness of opioids increased with decreases in the opioid's relative efficacy and with increases in the nociceptive stimulus intensity suggests that the relative efficacy of mu opioids as antinociceptive agents is greater in male than female rats.
Efficacy describes the ability of a drug to produce a response. The efficacy of mu-opioid agonists is an important consideration in their behavioral and clinical profile and can be measured at any functional endpoint between receptor occupancy and the resulting behavior. Measures of efficacy are dependent upon both the intrinsic efficacy specific to the drug and tissue parameters, in particular receptor number. This article considers measures of efficacy at both the earliest measurable event following mu-opioid receptor occupation by an agonist, namely the activation of G proteins as measured by the binding of [35S]GTPγS, and the final event, the observed behavior. Many mu-opioids show potency differences but often the maximal effect is the same. However, drugs can be separated in both G protein activity and behavioral assays by increasing the stringency of the assay or by reduction in the efficiency of the system following tolerance development or reduction in receptor number using irreversible antagonists. The order of efficacy is the same at the very separate stages of drug effect from receptor activation to behavioral endpoint, confirming the strength of the concept of intrinsic efficacy.
The development of the [35S]GTP--S binding assay has proven to be a valuable tool for studying opioid receptor mechanisms. In addition to being useful for medicinal chemistry applications, where it is important to determine if a compound is an agonist or an antagonist, this assay has provided new insights into the mechanisms of opioid tolerance and dependence. Importantly, this assay can provide a new dimension to structureactivity studies. The main purpose of this article is to review the recent work in our laboratory that used the [35S]GTP--S binding assay to advance our understanding of the four parameters associated with ligandreceptor interaction: potency, efficacy, intrinsic efficacy, and binding affinity, as well as molecular mechanisms associated with opioid tolerance and dependence. A major finding to emerge from our research is that the structureactivity of intrinsic efficacy is different from the typically studied structureactivity of binding affinity. The relative ease of determining the intrinsic efficacy of a compound with the [35S]GTP--S provides a simple approach to develop novel opioid ligands as both pharmacological tools and potential therapeutic agents.
Buprenorphine was given intravenously to produce analgesia in the immediate postoperative period, the dose being titrated against the response of each patient in order to obtain complete freedom from pain. In 50 patients following lower segment Caesarean section under general anaesthesia, buprenorphine in the dose range 0.4–7.0 mg was found to be a potent, long lasting and safe analgesic. Serial blood gas estimations performed on ten of the patients confkmed the clinically observed lack of respiratory depression.
The effects of the μ-opioid receptor agonists buprenorphine and morphine on immune and neuroendocrine functions through acute action in the rat mesencephalon periaqueductal gray (PAG) were evaluated. Buprenorphine is an analgesic recently approved for the treatment of drug dependency. In this study, it was shown that injection of an equianalgesic dose of buprenorphine (related to morphine) into the ventral–caudal PAG did not alter splenic NK cell, T cell, and macrophage functions, whereas morphine significantly (p<0.001) suppressed splenic NK cell cytotoxic activity (14–50% reduction), splenic and thymic T cell proliferation to concanavalin A (Con A, 43–76% reduction), antiTCR (T cell receptor) (85% reduction) and IL-2 (36–48% reduction), and macrophage functions including nitric oxide (36–41% reduction) and TNF-α production (26%), and phagocytosis of Candida albicans (39%). In addition, buprenorphine was associated with significant (p<0.0001) reductions in adrenocorticotropic hormone (ACTH) and corticosterone (CSO) plasma levels, without altering norepinephrine (NE) and serotonin splenic dialysate levels. In contrast, morphine significantly (p<0.0001) increased glucocorticoid and catecholamine levels in plasma and spleen dialysates, respectively. These results indicated that buprenorphine did not activate either the hypothalamic–pituitary–adrenal (HPA) axis with glucocorticoid release, or the sympathetic nerve (SNS) activity with bioamine production, and was not associated with immunosuppression. The lack of effects of buprenorphine on neuroendocrine systems may be related to its partial agonist properties, the absence of effects on immune system function, and may be associated with the reduction in craving observed in addictive disorders.
Experiments in a rat tail-withdrawal assay tested the hypothesis that the magnitude and pattern of antagonism of mu opiate agonists by the insurmountable mu opioid antagonist clocinnamox are inversely related to agonist efficacy. In addition, these experiments examined whether this antagonism could be quantified to yield apparent affinity and efficacy estimates for the pharmacological characterization of five opiate agonists. Etonitazene, etorphine, morphine, buprenorphine, and GPA 1657 produced dose-dependent increases in tail-withdrawal latency until 100% maximum possible effect (%MPE) was obtained. Morphine required a higher dose of clocinnamox for a 50% reduction in maximal antinociceptive effect than did buprenorphine or GPA 1657. In contrast, no dose of clocinnamox tested decreased the %MPE for etonitazene or etorphine. These data suggest a rank order of relative efficacy of etonitazene > or = etorphine > morphine > or = GPA 1657 > or = buprenorphine. Similarly, numerical analysis of these data yielded the following apparent affinity and efficacy estimates: etonitazene (0.38 mg/kg, 128); etorphine (0.68 mg/kg, 125); morphine (50 mg/kg, 38), GPA 1657 (6.6, 39); and buprenorphine (0.042 mg/kg, 2.2). These data illustrate that in vivo affinity and efficacy estimates for a number of agonists are remarkably similar across different methods of analysis and are useful for drug classification.
Loperamide, a butyramide derivative is a new agent for use in symptomatic control of acute non-specific diarrhoea and chronic diarrhoea. Unlike diphenoxylate or codeine, loperamide does not appear to exert opiate activity in man at normal therapeutic doses. In acute diarrhoea, loperamide provides more rapid control of symptoms than diphenoxylate when given in a flexible dosage according to unformed bowel movements, and in single dose studies 4mg loperamide has a much longer duration of effect than 5mg diphenoxylate. Loperamide is probably superior to diphenoxylate in providing symptomatic control of chronic diarrhoea such as that associated with chronic inflammatory bowel disease or following gastrointestinal surgery. It has been used for up to 3 years in such conditions without evidence of tolerance. The possibility of once daily dosage of loperamide in chronic diarrhoea is an advantage. Side-effects have not proved a problem.
Fenoterol, the 4-hydroxyphenyl derivative of orciprenaline, is a resorcinol derivative with relatively high selectivity for beta2-adrenoceptors. It is active in man after inhalation or oral administration and is indicated in the treatment of bronchospasm associated with asthma, bronchitis and other obstructive airway diseases. Clinical experience has shown that fenoterol is an effective bronchodilator with negligible effects on the cardiovascular system following aerosol administration of usual therapeutic doses. In children, inhaled fenoterol is effective in preventing exercise-induced asthma and administration of the aerosol in young children has been successfully used to terminate acute asthma attacks. In trials in adults, inhaled fenoterol was superior to placebo. In other controlled studies, it showed a tendency to cause a slightly greater maximum improvement in airway function as assessed spirometrically, and to have a longer duration of action than inhaled orciprenaline, salbutamol or terbutaline, although in these trials statistically significant differences were often not found. The onset of maximum effect is less rapid than with isoprenaline but is longer lasting. About 60% of the eventual maximum response to fenoterol is reached in the first few minutes after inhalation. Oral fenoterol is more effective than placebo, ephedrine or orciprenaline, and probably similar to salbutamol and terbutaline. Following usual aerosol doses, side-effects are minimal. Oral administration is associated with a higher incidence of side-effects than inhalation, including fine muscle tremor and tachycardia.
Butorphanol tartrate is a totally synthetic strong analgesic with both narcotic agonist and antagonist properties. When 1 or a few doses of butorphanol and other strong analgesic drugs such as morphine, pethidine or pentazocine were administered to patients with acute (in most cases postoperative) pain in a series of comparative studies, the analgesia produced was usually comparable in all aspects. Studies of analgesic efficacy and safety in patients with acute myocardial infarct pain have not been done. Only a small number of patients with chronic pain has received repeated doses of butorphanol over extended periods, and its relative efficacy, safety and tolerability when used in this manner needs further investigation. In other areas of use, 1 or 2 doses of butorphanol (1 or 2 mg) were at least as effective and safe as 40 or 80 mg of pethidine when used to relieve pain during active labor, but further studies utilizing neurobehavioral evaluations of the newborns for several days should be undertaken to confirm the apparent lack of adverse effects on the infant. In a few well designed anesthesia studies butorphanol appeared to be comparable to morphine or pethidine when used as a pre-anesthetic medication or as a component of 'balanced' anesthesia. Side effects with butorphanol have been typical of those usually associated with strong analgesics, sedation and nausea being the most frequent. As with other morphine-like agents, respiratory depression can occur, but unlike morphine (and in common with some other partial agonists-antagonists) the dose-response curve for this effect is plateau-like or bell-shaped, 'higher' doses (probably above about 1 to 2 mg in healthy subjects) producing a lesser effect than 'lower' doses. Butorphanol-induced respiratory depression was reversible in healthy subjects with moderate doses (up to 0.8 mg) of naloxone. Psychotomimetic reactions have been reported in some patients receiving butorphanol, and in some cases have been tentatively associated with butorphanol antagonism of previously chronically administered narcotics. However, this relationship is not well established, and the relative incidence of such reactions with butorphanol as compared with other drugs with both narcotic agonist and antagonist activity, such as pentazocine or nalorphine, needs clarification. Studies in animal models and in a few volunteers have suggested that butorphanol may have a lower dependence liability than narcotic drugs such as morphine or pethidine. It this is indeed the case it will offer an important advantage over these agents, but as with other drugs of this type only widespread use over several years will determine with any certainty the relative abuse and dependence potential of butorphanol.
Buprenorphine, a derivative of the morphine alkaloid thebaine, is a strong analgesic with marked narcotic antagonist activity. In studies in relatively small groups of postoperative patients with moderate to severe pain, one or a few doses of buprenorphine parenterally (by intramuscular or slow intravenous injection) or sublingually were at least as effective as standard doses of other strong analgesics such as morphine, pethidine or pentazocine, and buprenorphine was longer acting than these agents. Only a small number of patients with chronic pain have received repeated doses, but in such patients there was no need for increased doses during several weeks to months of treatment. Buprenorphine appears to produce side effects which are similar to those seen with other morphine-like compounds, including respiratory depression. There is apparently no completely reliable specific antagonist for buprenorphine's respiratory depressant effect, since even very high doses of the antagonist drug naloxone may produce only a partial reversal. The respiratory stimulant drug doxapram has overcome respiratory depression in volunteers and in a few patients in a clinical setting, but such studies have not been done in an overdose situation. Animal studies and a direct addiction study in a few volunteers suggest that the dependence liability of buprenorphine may be lower than that of other older morphine-like drugs. However, a slowly emerging abstinence syndrome did occur on withdrawal after very high doses administered for 1 to 2 months. A definitive statement on the drug's dependence liability and abuse potential cannot be made until it has had much wider use for a longer period of time.
1. Buprenorphine is a highly lipophilic derivative of oripavine. In rodent antinociceptive assays (writhing, tail pressure), buprenorphine had an action which was rapid in onset and of long duration; it was 25-40 times more potent than morphine after parenteral injection and 7-10 times more potent after oral administration. 2. The log dose-response relationship for buprenorphine was curvilinear in mouse and rat tail flick tests with the antinociceptive effect decreasing at higher, non-toxic doses. 3. Tolerance developed to the antinociceptive activity of buprenorphine in mice. 4. No signs of abstinence were observed on naloxone challenge or after abrupt withdrawal in monkeys receiving buprenorphine chronically for one month. 5. Buprenorphine antagonized the antinociceptive actions of morphine in mouse and rat tail flick tests but was an ineffective antagonist in the rat tail pressure test. 6. Buprenorphine precipitated signs of abstinence in morphine-dependent mice and monkeys but not in morphine-dependent rats. 7. Buprenorphine produced Straub tails in mice. This effect was not antagonized when the animals were pretreated with naloxone. However, in the rat tail pressure test high doses of diprenorphine antagonized established antinociceptive effects of buprenorphine. 8. It is concluded that buprenorphine represents a definite advance in the search for a narcotic antagonist analgesic of low physical dependence potential.
A series of morphine-like and nalorphine-like drugs were studied in the nondependent, morphine-dependent and cyclazocine-dependent chronic spinal dog. In the nondependent dog, three profiles of activity were found which could be utilized to distinguish between morphine, WIN 35, 197-2 and cyclazocine. Propiram, a prototypic partial agonist of the morphine type, produced morphine-like effects in nondependent dogs and both precipitated and suppressed abstinence in cyclazocine-dependent dogs as was needed to precipitate abstinence in morphine-dependent dogs. WIN 35, 197-2, a strong agonist in the guinea-pig ileum which has been shown to be resistant to antagonism by naloxone, neither precipitated nor suppressed morphine abstinence but suppressed cyclazocine abstinence. In the nondependent dog, it depressed the flexor reflex but not skin twitch reflex. Cyclazocine altered reflex activity much like WIN 35, 197-2 but produced tachycardia, tachypnea, mydriasis and canine delirum. The morphine and cyclazocine precipitated and withdrawal abstinence syndromes were qualitatively different. Twenty times as much naltrexone was needed to precipitate abstinence in morphine-dependent dogs. Nalorphine both precipitated and suppressed cyclazocine abstinence and appeared to be a partial agonist of the nalorphine-type. Morphine suppressed the cyclazocine abstinence syndrome. Cross-tolerance was not observed in ketocyclazocine-dependent dogs. These data are consistent with the hypothesis that there are strong and partial agonists of the mu and kappa types, and further, that physical dependence on morphine and cyclazocine is mediated through different receptors. WIN 35, 197-2 appears to be a pure strong agonist of the kappa type. Cyclazocine is a mu antagonist and mixed kappa and sigma agonist.
Three different syndromes produced by congeners of morphine have been identified in the nondependent chronic spinal dog. These syndromes have been attributed to interaction of agonists with three distinguishable receptors (mu, kappa and sigma). Morphine is the prototype agonist for the mu receptor, ketocyclazocine for the kappa receptor and SKF-10,047 for the sigma receptor. The morphine syndrome (mu) in the dog is characterized by miosis, bradycardia, hypothermia, a general depression of the nociceptive responses and indifference to environmental stimuli. Ketocyclazocine (kappa) constricts pupils, depresses the flexor reflex and produces sedation but does not markedly alter pulse rate or the skin twitch reflex. SKF-10,047 (sigma), in contrast to morphine and ketocyclazocine, causes mydriasis, tachypnea, tachycardia and mania. The effects of these three drugs can be antagonized by the pure antagonist naltrexone, indicating that they are agonists. Further, chronic administration of morphine, ketocyclazocine and SKF-10,047 induces tolerance to their agonistic effects. Morphine suppresses abstinence in morphine-dependent dogs while ketocyclazocine does not. Ketocyclazocine at best precipitated only a liminal abstinence syndrome in the morphine-dependent dog, indicating that it had little affinity for the morphine receptor. Ketocyclazocine thus appears to be a selective agonist at the kappa receptor. Further, it has been shown that buprenorphine is a partial agonist of the mu type which both suppressed and precipitated abstinence in the morphine-dependent dog while morphine and propoxyphene are stronger agonists. Apomorphine and SKF-10,047 produce similar pharmacologic effects suggesting that sigma activity may involve a dopaminergic mechanism.
Previous reports have shown that [Leu5]enkephalin or [Met5] enkephalin, endogenous delta receptor agonists, or synthetic analogues of these substances, can respectively produce a positive (i.e., increase) or negative (i.e., decrease) modulation of the antinociceptive potency of mu agonists such as morphine; such modulation is believed to be the result of interactions between delta and mu receptors. In spite of these studies showing modulation of mu agonist potency, it is unclear whether delta agonists can similarly modulate the antinociceptive efficacy of mu agonists. This question was addressed by using several levels of nociceptive stimulus intensity in mice. As the nociceptive stimulus intensity increased, the i.c.v. morphine dose-response line was shown to be displaced progressively to the right with decreasing maximal effect (i.e., decreased efficacy) a pattern typical of partial agonists. In contrast, the antinociceptive potency and efficacy of i.c.v. etorphine was unaffected by increasing the stimulus intensity, suggesting that this compound has higher efficacy than morphine in this nociceptive assay. Coadministration of delta opioid agonists produced leftward ([D-Pen2, D-Pen5] enkephalin) or rightward ([Met5]enkephalin) displacement of the morphine dose-response line (i.e., changes in potency). When the delta agonists were coadministered with morphine under conditions of high stimulus intensity, the maximal antinociceptive effects of i.c.v. morphine were increased or decreased from studies with morphine alone (i.e., change in efficacy). Both changes in potency and efficacy produced by the delta agonists, but not the direct antinociceptive effects of morphine, were blocked by the delta antagonist, ICI 174,864, suggesting that modulation occurred via the delta receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Morphine-treated rats exposed to restraint stress show potentiated magnitude and duration of analgesia compared to unstressed rats. The present study was performed to assess the pharmacological characteristics of stress-induced potentiation of opioid analgesia. We tested 10 opioids to determine whether restraint stress treatment would potentiate their ability to produce antinociception indexed by the tail-flick assay. We tested full mu, delta and kappa opioid receptor agonists (fentanyl, meperidine, DPDPE, U50488H, ethylketocyclazocine), and mixed agonist/antagonists representing a range of receptor selectivities and intrinsic activities (profadol, buprenorphine, pentazocine, butorphanol and nalbuphine). Dose-effect and time-response curves were generated for unrestrained and restrained rats after either subcutaneous (SC) and/or intracerebroventricular (ICV) injections. In restrained rats, all drugs except for SC-administered nalbuphine produced dose- and time-dependent analgesic effects of greater magnitude (1.5-3 times) than they produced in unrestrained rats. However, restrained rats given agonists with high intrinsic activity at the mu receptor displayed the most potent and consistent potentiation of analgesia compared to unrestrained controls. Our results suggest that activation of the mu receptor is of primary importance for restraint to potentiate analgesia, because restrained rats injected with delta and kappa agonists displayed potentiation of analgesia only at doses high enough to possibly exceed the selective activation of their respective receptor types.
Many studies of pain and nociception use short-lasting acute stimuli which may have limited relevance to prolonged or chronic pain states. Using extracellular single-unit recording in the dorsal horn of the rat lumbar spinal cord the present study examines the response of neurones to a long-lasting nociceptive stimulus, i.e., 50 microliter 5% formalin injected into the corresponding receptive field in the ipsilateral hind paw, and modulation of this response by an opioid. Formalin produced a distinct biphasic excitatory response in all convergent neurones tested; an immediate acute or phasic peak of neuronal firing (mean maximum 22 spikes/sec) 0-10 min post injection, and a second more prolonged tonic excitatory response (mean maximum 12 spikes/sec) over a period 20-65 min after formalin. Cells only activated by innocuous stimuli were not excited by formalin indicating the involvement of C fibre afferents in the excitatory response of convergent neurones to formalin. Both the biphasic nature and the time course of the neuronal response are similar to those observed in behavioural studies. Intrathecal DAGO (Tyr-D-AlaGlyMePheGly-ol), a potent and selective mu opioid receptor agonist, applied 20 min prior to formalin completely inhibited both peaks of excitation. Co-administration of intrathecal naloxone with the agonist restored the biphasic response. By contrast, when the administration of naloxone was delayed to 2 min post formalin so that inhibition of the first peak by DAGO pretreatment occurred, there was no subsequent second peak of activity although antagonism of the opioid would have occurred. When DAGO was applied 2 min post formalin so the initial acute response occurred, the inhibitory effect of the agonist on the second peak was far less. Thus the relative ability of DAGO to modulate the biphasic excitatory response of cells to formalin depends on whether the agonist is administered prior to or after the formalin and the appearance of the second peak may depend on the presence of the first. These results are discussed in light of the role of these neurones in nociception, opioid effects and changes in neural systems following peripheral stimuli.
Secondary and tertiary alcohols of general structures IV and V have been prepared by the demethylation of the corresponding bases I and II described in part II of this series. The phenols so obtained are analgesics of extremely high potency, up to an unprecedented 12,000 times that of morphine. The bases of this and earlier series have been converted into analogs of N-allylnormorphine and N-allylnorcodeine of general structures XI and XII via the N-cyanonor compounds and via novel N,N′-methylenebis compounds XIII resulting from the reaction of the bases I and II with methyl azodicarboxylate. Some bases of the series XII are morphine antagonists of unprecedented potency, up to 150 times that of N-allylnormorphine.
A series of secondary and tertiary alcohols have been prepared by the reduction and reaction with Grignard reagents of the aldehyde I (R = H), the ketones I (R = Me, Et, n-Pr, and Ph), and their 6,14-ethano analogs. The stereospecificity of the reactions is explained. In this way analgesics of very high potency, up to 500 times that of morphine, have been obtained.
1 In order to gain more insight into the mechanisms behind the actions of opiate partial agonists, an analysis of the dual agonist/antagonist properties of the partial agonist, buprenorphine, was made in conjunction with in vivo binding studies on the drug in the rat. 2 Buprenorphine revealed a bell-shaped dose-response curve for antinociception peaking at approx. 0.5 mg/kg subcutaneously. It antagonized morphine antinociception at doses which normally have agonistic effects and produced maximum antagonistic effects at doses above those having prominent agonistic activity. The withdrawal precipitating potency of buprenorphine as measured in highly morphine-dependent rats was present at doses above those having agonistic activity. The entire dose-response curve for buprenorphine was shifted symmetrically to the right by the opiate antagonist, naltrexone. 3 The dose-dependent occupation of receptors in vivo by buprenorphine seemed to be almost complete over the agonist dosage range; almost no further receptor occupation over the antagonist range was seen. 4 The possibility is discussed that site-to-site receptor interactions leading to cooperativity of effect may be the best explanation of these results.
The binding of the mixed opiate agonist-antagonist 3H-buprenorphine to rat CNS membranes was stereospecific, saturable and had high affinity. Maximal specific binding of 3H-buprenorphine at 25°C was reached by 30 minutes and dissociation from the receptor was slow. 3H-Buprenorphine labelled a single class of high affinity binding sites (KD = 0.86nM, Bmax = 30.2pmole/g tissue). The Bmax for 3H-buprenorphine was about two times that for the μ-opiate receptor drugs 3H-naloxone and 3H-dihydromorphine, and three times the Bmax for the σ-opiate receptor ligand 3H-D-Ala2, L-Met5-enkephalinamide. The regional distribution of 3H-buprenorphine binding was qualitatively similar to the distribution of 3H-naloxone and 3H-dihydromorphine binding. Changing the incubation temperature from 25°C to 37°C increased 3H-buprenorphine binding in all regions of the CNS yet decreased 3H-naloxone and 3H-dihydromorphine binding in most regions. These effects of increasing temperature were a result of changes in 3H-opiate affinity for the receptor with no significant changes in receptor number. Sodium chloride (154mM) enhanced both 3H-buprenorphine and 3H-naloxone binding, and decreased 3H-dihydromorphine binding. The potency of opiate alkaloids and peptides in displacing 3H-buprenorphine was relatively weak with IC50 values ranging between 40nM and 600nM. Furthermore displacement curves were shallow, yielding curvilinear Scatchard plots. Buprenorphine was very potent in displacing 3H-naloxone (IC50 = 0.52nM), 3H-dihydromorphine (IC50 = 1.17nM) and 3H-D-Ala2, L-Met5-enkephalinamide (IC50 = 0.47nM). These findings suggest that buprenorphine binds to both μ- and δ-opiate receptors.
Buprenorphine, a mixed opioid agonist-antagonist, is being investigated as a treatment for opioid dependence. This study compared the acute subjective and physiological effects of sublingual buprenorphine to those of p.o. methadone over a wide range of doses and compared the ability of both drugs to alter the effects of an opioid challenge. Male inpatient volunteers (n = 9) with histories of opioid abuse participated in this double-blind, double-dummy study. Sublingual buprenorphine (0, 0.5, 2, 8, 16 and 32 mg) and p.o. methadone (3.75, 15 and 60 mg) were administered once weekly according to a Latin-square design, and subjects were monitored on a variety of physiological and subjective measures. Twenty-four hours later, subjects were tested with ascending doses of i.m. hydromorphone (0, 1 and 4 mg) given 45 min apart. Buprenorphine and methadone produced typical opioid agonist effects of long duration, including pupillary constriction, respiratory depression and elevations on subject-rated and observer-rated indices of euphoria, sedation and opioid-like symptoms. The buprenorphine dose-effect curves were nonlinear and maximal effects for most physiological and subjective measures were observed between 4 and 8 mg, with no greater effects observed at higher doses. The methadone dose-effect curves were linear across the range of doses tested. High doses of buprenorphine and methadone both attenuated the response to hydromorphone challenge 24 hr later. These data indicate that there is a ceiling on the effects of buprenorphine in humans that may reduce its abuse liability and increase its safety, and indicate that opioid blockade occurs after acute administration of buprenorphine or methadone.
The ability of mu-opioid agonists to activate G proteins has been demonstrated by studying the binding of the GTP analogue guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTP gamma S) to membranes from the human neuroblastoma SH-SY5Y cell line. The potent opioid agonist fentanyl caused an approximate doubling of basal [35S]GTP gamma S binding in a naloxone-sensitive manner, confirming this to be an opioid receptor-mediated process. The presence of GDP was necessary to observe this effect. Pretreatment of the cells with pertussis toxin (100 ng/ml, for 24 hr) completely prevented the fentanyl-stimulated increase in [35S]GTP gamma S binding and lowered the basal binding of [35S]GTP gamma S. These latter data suggest an involvement of Gi and/or Go proteins and their activation by added membrane-bound receptors even in the absence of agonist. The order of potency of a series of opioid agonists in stimulating the binding of [35S]GTP gamma S was buprenorphine > cyclazocine = levallorphan > nalorphine > [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO) > fentanyl > morphine > pentazocine. DAMGO, fentanyl, and morphine were full agonists but the remaining compounds showed decreasing levels of intrinsic activity in the order buprenorphine > pentazocine > cyclazocine = nalorphine > levallorphan. The opioid antagonist naloxone was without effect. Under the conditions of the [35S]GTP gamma S assay, binding of agonists was to a high affinity site, indicating that a high agonist affinity state of the mu-opioid receptor is responsible for the observed stimulation of [35S]GTP gamma S binding. The level of [35S]GTP gamma S binding (597 fmol/mg of protein) stimulated by DAMGO was 2-fold greater than the maximal number of mu-opioid agonist binding sites (Bmax) determined using [3H]DAMGO (254 fmol/mg of protein). The opioid agonist-mediated stimulation of [35S]GTP gamma S binding in SH-SY5Y cell membranes thus provides a "functional" measure of agonist occupation of mu-opioid receptors and offers a simple method for the determination of efficacy and intrinsic activity of mu-opioid agonists.
The apparent in vivo dissociation constant (KA) and relative efficacy values for alfentanil, etonitazene, morphine, and nalbuphine were determined by comparing the effects of these agonists in the presence of buprenorphine with the effects of these agonists alone in the rhesus monkey tail-withdrawal procedure. Initial time course studies of buprenorphine alone indicated that 3.2 and 10 mg/kg produced increases in tail-withdrawal latencies when studied with 48 degrees C water for 48 hr. No increases in tail-withdrawal latency were found with either dose studied with 55 degrees C water. Buprenorphine produced dose-dependent shifts to the right for the antinociceptive effects of alfentanil, etonitazene, morphine and nalbuphine 72 hr after administration and decreased the maximal effects of morphine in 48 degrees C water and those of alfentanil and etonitazene in 55 degrees C water. Buprenorphine administration decreased the receptors available for agonist interaction to approximately 2%. The average apparent in vivo dissociation constant (KA) values for alfentanil, etonitazene, morphine and nalbuphine were 3.3, 0.073, 60 and 31 mg/kg, respectively. High efficacy estimates were determined for alfentanil (149-203) and etonitazene (174-203), whereas lower efficacy estimates were determined for nalbuphine (57) and morphine (17). The apparent in vivo dissociation constant of a pseudoirreversible antagonist (KB) value for buprenorphine averaged 0.15 mg/kg across agonists, temperatures and buprenorphine doses. These data extend and emphasize the significance of in vivo estimates of affinity and relative efficacy for drug classification.
To assess effects of stimulus intensity, dose-response curves in rats for radiant heat-evoked withdrawal of the hind paw was assessed after the intrathecal (i.t.) injection of sufentanil and morphine, mu-opioid agonists differing in intrinsic activity, at Low, Medium, and High stimulus intensities. Baseline latencies observed at the 3 intensities were: low = +/- 0.3; medium = 8.9 +/- 0.2; high = 5.7 +/- 0.1 sec. After i.t. administration of sufentanil or morphine, there was a right shift in the dose-response curves with morphine exhibiting a greater magnitude right shift than that of sufentanil. Dose ratios (ED 50 Medium/ED 50 Low and ED 50 High/ED 50 Low) with 95% CI for sufentanil were, respectively, 2.5 (2.2-2.9) and 7.7 (6.7-8.9), and the dose ratio for morphine (ED 50 Medium/ED 50 Low) was 34 (28-41). At the highest intensity, due to a plateau in the morphine dose-response curve, ED 50 and dose ratio calculations could not be performed. The present study supports the pharmacological model of receptor occupancy, such that the higher efficacy receptor agonist, sufentanil, demonstrated a lesser magnitude right shift than the lower efficacy agonist, morphine, while at the high stimulus intensity, morphine but not sufentanil, was a partial agonist.
Large-scale placebo controlled clinical trials assessing the efficacy of medications for the treatment of drug dependence have generally been limited to alcohol, cocaine and nicotine dependent populations. The purpose of the present study was to assess the early (1-2 week) clinical effectiveness of buprenorphine versus placebo in an opioid dependent population. The study used a parallel-group design with a behavioral choice component to compare buprenorphine (a mu-opioid partial agonist) to placebo for the treatment of opioid dependence. Opioid dependent volunteer patients participated in a 14-day study to assess the effectiveness and patient acceptance of this new pharmacotherapy for the treatment of opioid dependence. Patients were randomly assigned to placebo (n = 60) or 2 mg (n = 60) or 8 mg (n = 30) daily sublingual buprenorphine. All doses were administered double-blind. On days 6-13 all patients could request a dose change, knowing that their new dose would be randomly chosen from the remaining 2 alternatives. Compared to placebo, patients given buprenorphine (independent of dose) showed greater time on initial dose, requested fewer dose changes, used less illicit opioids (assessed by urinalysis), and rated dose adequacy higher. These results demonstrate that a placebo controlled study with a behavioral choice component is an effective means of assessing the potential efficacy and acceptability of new pharmacotherapies for opioid dependence.
G protein activation by different mu-selective opioid agonists was examined in rat thalamus, SK-N-SH cells, and mu-opioid receptor-transfected mMOR-CHO cells using agonist-stimulated guanosine-5'-O-(gamma-thio)-triphosphate ([35S]GTP gamma S) binding to membranes in the presence of excess GDP. [D-Ala2, N-MePhe4, Gly5-ol]Enkephalin (DAMGO) was the most efficacious agonist in rat thalamus and SK-N-SH cells, followed by (in rank order) fentanyl = morphine > > buprenorphine. In mMOR-CHO cells expressing a high density of mu receptors, no differences were observed among DAMGO, morphine or fentanyl, but these agonists were more efficacious than buprenorphine, which was more efficacious than levallorphan. In all three systems, efficacy differences were magnified by increasing GDP concentrations, indicating that the activity state of G proteins can affect agonist efficacy. Scatchard analysis of net agon stimulated [35S]GTP gamma S binding revealed two major components responsible for agonist efficacy differences. First, differences in the KD values of agonist-stimulated [35S]GTP gamma S binding between high efficacy agonists (DAMGO, fentanyl, and morphine) and classic partial agonists (buprenorphine and levallorphan) were observed in all three systems. Second, differences in the Bmax value of agonist-stimulated [35S]GTP gamma S binding were observed between DAMGO and morphine or fentanyl in rat thalamus and SK-N-SH cells and between the high efficacy agonists and buprenorphine or levallorphan in all three systems. These results suggest that mu-opioid agonist efficacy is determined by the magnitude of the receptor-mediated affinity shift in the binding of GTP (or[35S]GTP gamma S) versus GDP to the G protein and by the number of G proteins activated per occupied receptor.
This study examined the signal transduction correlates of mu opioid agonist efficacy in two systems: mu receptor-transfected mMOR-CHO cell and rat thalamic membranes. The potency and maximal stimulation of [35S]GTP gamma S binding by various agonists was measured in the presence of excess GDP and compared with receptor binding affinity under identical assay conditions. Results showed that the relative maximal stimulation produced by these agonists was greater in mMOR-CHO cell than in rat thalamic membranes; some drugs that were full agonists in mMOR-CHO cells were partial agonists in the thalamus, and some partial agonists in the transfected cells were full antagonists in the thalamus. Furthermore, there was receptor reserve for G-protein activation by some agonists in mMOR-CHO cell membranes, but no receptor reserve was detected in rat thalamic membranes. Saturation analysis of agonist-stimulated [35S]GTP gamma S binding revealed that full agonists produced both a higher Bmax and apparent affinity of [35S]GTP gamma S binding than partial agonists. Correlation of the Bmax and KD of agonist-stimulated [35S]GTP gamma S binding with agonist intrinsic efficacy revealed only a moderate correlation with either parameter alone, but a highly significant correlation (r > 0.9) with a combination of the two parameters (Bmax/KD). These results suggest that the intrinsic efficacy of agonists at G-protein-coupled receptors is determined primarily by the ability of the agonist-occupied receptor to promote high-affinity GTP binding to the G-protein and to catalytically activate a maximal number G-proteins.
In this review we critically appraise the value of some phasic and tonic nociceptive tests as models for differentiating the antinociceptive effects of opioid agonists. Using heat-evoked withdrawal of the hind paw or tail of a rodent, several early studies have assessed the effects of stimulus intensity upon antinociceptive potency of opioid agonists. After intrathecal (i.t.) administration of either morphine or sufentanil, for example, for any incremental change in stimulus intensity, the degree of right shift in the dose-response relationship was greater for morphine than for sufentanil. At first glance, such data appear to provide robust support for the pharmacological model of fractional receptor occupancy (FRO), which, according to the historical tenets of classical receptor theory, describes the relationship between intrinsic efficacy and the total receptor concentration. However, new data which elegantly characterize the relative contribution of small calibre unmyelinated and myelinated nociceptive afferents in mediating thermal-evoked responses challenge the exclusivity of such explanations with origins in classical theory. Within our review we report the results of experiments which provide direct electrophysiological evidence that noxious skin heating at a low rate activates C-polymodal nociceptors, but does not effectively activate A-delta mechanothermal nociceptors. In contrast, a high rate of skin heating activates both nociceptor classes, but produces a more intense activation of A-delta nociceptors that occurs after a shorter onset latency compared with the activation of C-fibre nociceptors. Thus, in direct challenge to the traditional model of FRO, a shift in the dose-response relationship of morphine to the right with a reduction in efficacy, may reflect the limited effectiveness of morphine to attenuate the A-delta-mediated component which assumes increasing dominance at high intensity heating. In our appraisal of other nociceptive models we provide an in-depth characterization of afferent processing in the early neonate rat, in which opioids have been tested in both phasic (tail flick and hot-plate) and tonic (formalin) tests. Afferent processing in this model is typified by several behavioural, anatomical and functional features which, although not pathological, are characteristic of those observed in models of nerve injury using the adult rat. Notably, these features include a lack of segmental inhibition ('disinhibition') and afferent input in large diameter myelinated fibres which make synaptic contacts within superficial laminae of the dorsal horn that in the adult are predominantly nociceptive. Paradoxically, because this paradigm demonstrates increased sensitivity to the antinociceptive effects of opioids it may have special merit as a model of tonic pain. It was recently announced that the i.t. administration of pertussis toxin (PTX) caused hyperalgesia and allodynia that appears similar to the symptoms reported by patients suffering from neuropathic pain. Unlike the effects of other opioids so far tested, buprenorphine-induced antinociception is not blocked in this model. This is an exciting finding and provides new optimism that some opioids, notably buprenorphine, may have a special role in managing some types of neuropathic pain.
Unlabelled:
We examined the effects of several opioids that vary in intrinsic efficacy at the mu-opioid receptor alone and in combination with morphine in a rat warm water tail withdrawal procedure using 50 degrees C and 52 degrees C water (i.e., low- and high-stimulus intensities). Morphine, levorphanol, dezocine, and buprenorphine produced dose-dependent increases in antinociception using both stimulus intensities. Butorphanol produced maximal levels of antinociception at the low, but not at the high, stimulus intensity, whereas nalbuphine failed to produce antinociception at either stimulus intensity. For cases in which butorphanol and nalbuphine failed to produce antinociception alone, these opioids dose-dependently antagonized the effects of morphine. When levorphanol, dezocine, and buprenorphine were combined with morphine, there was a dose-dependent enhancement of morphine's effects. Similar effects were obtained at the low-stimulus intensity when butorphanol was administered with morphine. In most cases, the effects of these combinations could be predicted by summating the effects of the drugs when administered alone. These results indicate that the level of antinociception produced by an opioid is dependent on the intrinsic efficacy of the drug and the stimulus intensity. Furthermore, the level of antinociception produced by the opioid, not necessarily the opioids' intrinsic efficacy, determines the type of interaction among opioids.
Implications:
Compared with high-efficacy opioids, lower efficacy opioids produce lower levels of pain relief, especially in situations of moderate to severe pain. When opioids are given in combination, the effects can only be predicted on the basis of the antinociception obtained when the drugs are administered alone.
This study examines the possibility that oripavine opioid receptor agonists bind equally to both high and low affinity states of the mu-opioid receptor. Studies were performed in C6 cells expressing mu- or delta-opioid receptors; high and low agonist affinity states of the receptors were defined by the absence and presence, respectively of Na+ ions and the GTP analog Gpp(NH)p. At the mu-opioid receptor dihydroetorphine and etorphine were full agonists, buprenorphine had moderate efficacy while diprenorphine was an antagonist. At the delta-opioid receptor, dihydroetorphine, etorphine, and diprenorphine had moderate efficacy while buprenorphine was an antagonist. The binding affinities of the oripavines at the mu-opioid receptor decreased only one to 2-fold in the presence of NaCl and Gpp(NH)p. In contrast, decreases in oripavine affinity at the delta-opioid receptor correlated with delta-opioid receptor efficacy. The ability of oripavine agonists to bind with high affinity to the low agonist affinity state of the nu-opioid receptor may explain the high potencies of these compounds in vivo.
Buprenorphine (BUP) is an oripavine analgesic that is beneficial in the maintenance treatment of opiate-dependent individuals. Although BUP has been studied extensively, relatively little is known about norbuprenorphine (norBUP), a major dealkylated metabolite of BUP. We now describe the binding of norBUP to opioid and nociceptin/orphanin FQ (ORL1) receptors, and its effects on [(35)S]guanosine-5'-O-(gamma-thio)triphosphate ([(35)S]GTP gamma S) binding mediated by opioid or ORL1 receptors and in the mouse acetic acid writhing test. Chinese hamster ovary cells stably transfected with each receptor were used for receptor binding and [(35)S]GTP gamma S binding. NorBUP exhibited high affinities for mu-, delta-, and kappa-opioid receptors with K(i) values in the nanomolar or subnanomolar range, comparable to those of BUP. NorBUP and BUP had low affinities for the ORL1 receptor with K(i) values in the micromolar range. In the [(35)S]GTP gamma S binding assay, norBUP displayed characteristics distinct from BUP. At the delta-receptor, norBUP was a potent full agonist, yet BUP had no agonist activity and antagonized actions of norBUP and DPDPE. At mu- and kappa-receptors, both norBUP and BUP were potent partial agonists, with norBUP having moderate efficacy and BUP having low efficacy. At the ORL1 receptor, norBUP was a full agonist with low potency, while BUP was a potent partial agonist. In the writhing test, BUP and norBUP both suppressed writhing in an efficacious and dose-dependent manner, giving A(50) values of 0.067 and 0.21 mg/kg, s.c., respectively. These results highlight the similarities and differences between BUP and norBUP, each of which may influence the unique pharmacological profile of BUP.
Recent studies indicate that mu opioids are generally more potent and effective as antinociceptive agents in male than female rodents.
To evaluate the influence of sex on the development of tolerance to the antinociceptive effects of morphine and cross-tolerance to the lower efficacy mu opioids buprenorphine and dezocine in F344 and Lewis rats.
Using a warm-water tail-withdrawal procedure, the antinociceptive effects of morphine, buprenorphine and dezocine were determined before and during chronic morphine (5, 10 and 20 mg/kg, b.i.d., for 7 and 14 days) administration.
Under acute conditions, morphine was more potent in males and during chronic morphine administration tolerance development was generally greater in males. As males were more sensitive to the acute effects of morphine, the functional chronic morphine dose (i.e., chronic morphine dose/acute morphine ED50) administered to males was larger than in females. Analyses of the relationship between the functional chronic morphine dose and tolerance indicated that morphine tolerance development was comparable in males and females. Under acute conditions, buprenorphine and dezocine were more potent and effective in males. During chronic morphine administration, cross-tolerance was conferred to these opioids as evidenced by rightward, and in some cases downward, shifts in their dose-effect curves. Decreases in the maximal effects produced by buprenorphine and dezocine were more frequently observed in females.
That comparable levels of morphine tolerance were obtained in males and females when the functional chronic morphine dose was taken into consideration suggests that the mechanism underlying tolerance is not sex-dependent. Sex differences in the effectiveness of buprenorphine and dezocine when administered acutely and during chronic morphine administration further suggest that these opioids have lower efficacy at the mu opioid receptor in females.
In Germany and many other countries, buprenorphine has been used for a long time for the management of pain in both cancer and non-cancer patients. Although a transdermal delivery system for buprenorphine (Transtec) has recently been introduced, the clinical experience in daily practice with this drug, delivered in a matrix patch, is only now being evaluated. In preliminary data from a survey of 3,255 patients with chronic pain, 26% had cancer pain, while the most common diagnoses of the other respondents included back pain (33%), osteoarthritis (22%), osteoporosis (17%), and neuropathic pain (10%, multiple entries). Before being switched to the buprenorphine patch, most patients had been pretreated with World Health Organization (WHO) Step II opioids (47%) or WHO Step III opioids (18%), including tramadol (in 35% of patients) and a tilidin/naloxone combination (15%); 9% had not been prescribed any opioids in advance of receiving transdermal buprenorphine. Most patients (77%) in the survey had been started on the lowest dose of the buprenorphine patch (35 microg/h), and nearly half (49%) were placed on adjuvant analgesics, including tramadol or tilidin/naloxone. Pain relief was rated as good or very good by 81% of the respondents. Adverse effects were similar to those seen on other opioids, although their intensity was mild in most cases. Local side effects, including erythema (4% of cases) and pruritus (1%), were transitory. Based on the survey results, transdermal buprenorphine is considered an effective opioid treatment for patients with stable cancer and non-cancer pain; it may prove particularly useful in patients who have experienced side effects taking oral analgesic preparations, as well as in those who are taking extensive co-medications.