Nalbuphine

Nalbuphine is a potent analgesic with a low side effect and dependence profile in animals and man. Nalbuphine is distinguished from other agonist/antagonist analgesics in having greater antagonist activity and fewer behavioral effects at analgesic doses than pentazocine, butorphanol or buprenorphine. At equi-analgesic doses, nalbuphine is quantitatively similar to nalorphine in regard to its large ratio of antagonist to analgetic activity. Clinical studies have confirmed this balance of strong antagonist to analgesic activity. Nalbuphine has been shown to effectively antagonize the respiratory depressant activity of narcotic analgesics while concomitantly adding to their analgetic responses. Unlike nalorphine or pentazocine, nalbuphine produces few overt behavioral or autonomic effects in animals at doses over 300 times its analgesic range. These findings are confirmed by clinical results which show that nalbuphine produces few psychotomimetic effects, even at elevated dose levels, in contrast to nalorphine or pentazocine. Nalbuphine produces limited respiratory depression in animals and in man. Significant cardiovascular effects have not been found. Nalbuphine was found to produce significantly less inhibition of gastrointestinal activity than any of the clinically useful narcotic or agonist/antagonist analgesics tested in animals. Nalbuphine's analgetic effects are reversed by naloxone doses similar to those which reverse nalorphine's agonist effects. Results in this and other tests suggest that nalbuphine is primarily a kappa-agonist/mu-antagonist analgesic. Unlike pentazocine or buprenorphine, nalbuphine does not suppress the narcotic abstinence syndrome in partly-withdrawn morphine-dependent animals or man. Rather, due to nalbuphine's strong antagonist activity, analgesic-range doses of nalbuphine severely exacerbate the withdrawal syndrome in partly-withdrawn mice, monkeys and humans. Nalbuphine also precipitates a strong abstinence response in non-withdrawn morphine-dependent animals and man. In post-addict humans, analgesic-range doses of nalbuphine are perceived as minimally morphine-like, but higher doses are judged to be progressively more nalorphine-like (i.e. dysphoric), which further limits nalbuphine's abuse potential in drug-seeking individuals. Primary dependence studies have demonstrated that physical dependence is possible at high dose levels that produce marked side effects. Other studies show that dependence is unlikely to be of significance within nalbuphine's usual analgesic range. Six-month studies in patients with chronic pain have confirmed that analgesic tolerance or physical dependence is uncommon.(ABSTRACT TRUNCATED AT 400 WORDS)     

Review of self-administration

The reinforcing properties of drugs can be evaluated pre-clinically using self-administration procedures in laboratory animals. This paper reviews self-administration studies of the four opioid agonist/antagonist analgesics pentazocine, butorphanol, nalbuphine and buprenorphine, and compares these results to those from studies of morphine and cyclazocine. All four agonist/antagonists possess reinforcing properties under at least some test conditions. In this respect they more resemble morphine than cyclazocine. These results suggest that they all may have some potential for recreational use. On the other hand, some data point to a lower reinforcing efficacy for these agonist/antagonists than for the pure agonists such as morphine. Studies comparing the reinforcing efficacy among the agonist/antagonists are also reviewed, however more data are needed before definitive conclusions can be drawn within the class.     

Discriminative stimulus effects of buprenorphine in the rat

 Buprenorphine, a potent ”low efficacy” or ”partial” morphine-like opioid agonist, has morphine-like discriminative effects in animals and humans discriminating morphine or a related drug. The purpose of the present study was to characterize further the discriminative effects of buprenorphine in subjects trained to discriminate buprenorphine itself. Rats trained to discriminate between SC injections of saline and either 0.03 or 0.1 mg/kg buprenorphine generalized completely to morphine and to other morphine-like agonists. These drugs were approximately 3 times more potent in the rats trained with 0.03 mg/kg buprenorphine than in those trained with 0.1 mg/kg; however, the potency of buprenorphine itself did not differ significantly between groups. Indicative of efficacy differences among mixed-action opioids, rats discriminating 0.03 mg/kg buprenorphine generalized completely to butorphanol and pentazocine and partially to nalbuphine, whereas those discriminating 0.1 mg/kg generalized completely to butorphanol, partially to pentazocine, and little to nalbuphine. Stimulus control of behavior by 0.1 mg/kg buprenorphine was blocked surmountably by low doses of antagonists, stereoselective, and pharmacologically selective. These results are consistent with those of other studies showing that the discriminative effects of buprenorphine are morphine-like and mediated by the mu-opioid receptor, and extend the conditions under which this has been demonstrated to stimulus control maintained by buprenorphine itself. Received: 18 September 1996 / Final version: 6 November 1996     

Dezocine. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy

Dezocine is an analgesic agent with opioid agonist and antagonist activity. After parenteral administration of therapeutic doses it is approximately equipotent with morphine, and has proved at least as effective an analgesic as morphine, pethidine (meperidine) and butorphanol in moderate to severe postoperative pain. However, preliminary pharmacodynamic data indicate that the ceiling of analgesic activity of dezocine occurs at a higher level of analgesia than that of reference agonist/antagonist agents. Also, the drug exhibited a morphine-like degree of anaesthetic-sparing activity in animals. Although long term data are very limited, single doses of dezocine are well tolerated, with mild and transient sedation and gastrointestinal upset the principal adverse effects. As with some other agonist/antagonist analgesics, a 'ceiling' effect to dezocine-induced respiratory depression occurs with increasing dosage, beyond which further depression has not been observed. In single analgesic doses, however, dezocine is a slightly more potent respiratory depressant than morphine. Clinically important haemodynamic changes have not been observed with usual analgesic doses of dezocine. As an agonist/antagonist opioid, the dependence liability of dezocine would be expected to be lower than that of pure agonist opioids, but extended clinical use is required before more definitive conclusions can be drawn in this regard. Unlike older drugs of its type, dezocine produced opiate-like subjective effects and was identified as morphine-like by drug abusers. Thus, provided the promising conclusions of currently available clinical studies are confirmed with its wider use, dezocine should be a useful additional agent for the treatment of moderate to severe postoperative pain.     

Quantification of the morphine reversal activity of opioid agonists/antagonists and naloxone by using a rabbit tooth pulp procedure

The rabbit tooth pulp procedure was used to determine the potencies and durations of morphine reversal by naloxone, buprenorphine, nalbuphine, butorphanol, and pentazocine. Cumulative doses (mg/kg) required to double the number of morphine-depressed respirations per minute (RPM) (ED 2 X) and to reduce morphine-elevated lick/chew (L/C) volts by one-half (ED 1/2) were determined. These doses were naloxone 0.003, 0.013; buprenorphine 0.030, 0.130; nalbuphine 0.130, 0.520; butorphanol 0.120, 0.630; pentazocine 1.10, 0.150. The antinociceptive effects of these compounds were compared by determining the cumulative dose required to achieve the highest percentage maximum possible effect (% MPE) as determined by the elevation of lick/chew threshold volts from control volts in morphine-free rabbits: naloxone 6% at 0.0005 mg/kg; buprenorphine 69% at 0.075 mg/kg; nalbuphine 32% at 0.150 mg/kg; butorphanol 32% at 0.150 mg/kg, and pentazocine 12% at 1.55 mg/kg. The durations (min) of reversal of morphine RPM and morphine L/C volts were also determined: naloxone 33, 30; buprenorphine 240, 240; nalbuphine 120, 120; butorphanol 90, 45; pentazocine 60, 15. It is suggested that the rabbit tooth pulp assay is a sensitive and reliable assay to evaluate and quantitate compounds for opioid agonist/antagonist activity.     

Substitution and primary dependence studies in animals

The mixed agonist-antagonist analgesics buprenorphine, butorphanol, nalbuphine, pentazocine and picenadol were compared to the prototype mu and kappa agonists morphine and Mr 2033, respectively, in the following tests in rhesus monkeys: overt behavioral effects upon acute administration in drug-naive animals; discriminative stimulus properties in monkeys trained to respond to either etorphine or ethylketazocine; self-administration of the test agent relative to codeine; single dose suppression and precipitation in withdrawn and non-withdrawn morphine-dependent monkeys, respectively; and primary addiction studies in drug-naive animals. Whereas both buprenorphine and nalbuphine precipitate withdrawal in morphine-dependent monkeys, withdrawal following chronic administration of buprenorphine resulted in no observable signs of abstinence, while nalbuphine withdrawal was similar to that seen in morphine-dependent monkeys. Butorphanol, pentazocine and picenadol all produced mild dependence of the kappa-type; that is, natural withdrawal behavior similar to that seen following chronic Mr 2033 administration.     

Clinical observations of agonist-antagonist analgesic dependence

The agonist-antagonist opioids are clinically effective analgesics with generally low abuse potential. Four agonist-antagonists are currently available for use as analgesics. Pentazocine, butorphanol and nalbuphine produce morphine-like effects in low doses and, to varying degrees, dysphoric effects as the dose is increased. Buprenorphine, an antagonist opioid of slow onset but long duration of action, produces morphine agonist effects at lower doses, and as the dose is increased, antagonist effects with minimal or no dysphoria. Clinical experience with pentazocine indicates that abuse is possible and consists of two main types: misuse (and abuse) of the drug alone by patients during treatment for pain and, abuse of the drug, often taken together with other psychoactive agents, as a substitute for the preferred drug of abuse. Few reports of abuse have appeared for butorphanol, nalbuphine and buprenorphine; however, considerable care is recommended in their use in patients, especially where there is the possibility for abuse as might occur in patients who require long-term treatment, with a history of drug abuse, and where the drug is easily obtained.     

Nalbuphine. A preliminary review of its pharmacological properties and therapeutic efficacy

Nalbuphine is an agonist/antagonist analgesic. After parenteral administration of 'usual' doses it is approximately equipotent in analgesic activity to morphine on a weight basis. In studies in patients with moderate to severe pain, usually following surgery, the characteristics of analgesia with nalbuphine were comparable to those seen with equianalgesic doses of morphine or pentazocine. It also appears to produce satisfactory anaesthesia when used as a component of a 'balanced' anaesthesia technique, although a relatively low 'ceiling' effect for reduction of anaesthetic requirements with nalbuphine may limit its usefulness in this regard. As with other agonist/antagonist analgesics, a 'ceiling' effect to nalbuphine-induced respiratory depression is also seen, beyond which further depression does not readily occur. However, with usual analgesic doses, respiratory depression seen with nalbuphine is comparable to that with morphine. Important haemodynamic changes have not occurred after usual doses of nalbuphine, even in patients with cardiac disease. Like other agonist/antagonist analgesic drugs, the abuse potential of nalbuphine seems relatively low, but only wider clinical use for longer periods can establish this with certainty. Thus, nalbuphine appears to offer a useful alternative to morphine in patients with moderate to severe pain.     

The clinical usefulness of agonist-antagonist analgesics in acute pain

The opioid agonist-antagonists are a heterogeneous group of compounds capable of providing analgesia sufficient to treat moderate to severe acute pain. Pentazocine, butorphanol and nalbuphine produce subjective effects which are quite different from those of morphine. Lack of mood elevation and occasional dysphoria may contribute to a lower level of patient acceptance, but all of these analgesics are significantly safer than the pure agonists. Doses in the therapeutic range are unlikely to produce dangerous levels of respiratory depression in most patients. Other opioid side-effects such as nausea, constipation and biliary spasm appear to be less frequent as well.

The mu partial agonist buprenorphine shares many of the safety advantages of the older drugs, and its subjective effects appear more morphine-like. It is not clear whether mu partial agonists have real clinical advantages over kappa-type analgesics.

All of these drugs are opioid antagonists and are able to precipitate abstinence in individuals with significant prior exposure to opiates. Neither absolute potency nor the ratio of agonist to antagonist effect are predictors of therapeutic usefulness.

There is now an enormous amount of clinical experience with the agonist-antagonists. In many, but not all, clinical situations they are acceptable alternatives to the morphine-like drugs.     

The clinical usefulness of agonist-antagonistic opioid analgesics in chronic pain

The mixed agonist-antagonist analgesics do not have a major role in the treatment of chronic pain. Pentazocine, the first and most widely used of this group of drugs has two major limitations: by mouth it is not a strong analgesic, but is closer in efficacy to the peripherally acting drugs aspirin and paracetamol than the weak opioids; and its use is associated with psychotomimetic side effects in 10–20 percent of patients. The weak opioid analgesics codeine and dextropropoxyphene are more effective and better tolerated than pentazocine.

Buprenorphine is the most useful of the agonist-antagonists in chronic pain patients. It is potent, long-acting (6–9 h) and effective when given sublingually. However, it has a limited effective dose range and produces the same side effects as morphine-like drugs, possibly more frequently at equianalgesic doses. It may be used in the treatment of cancer pain, or in patients with chronic arthritides or other forms of chronic non-cancer pain who require a potent conventional analgesic, as an alternative to the weak opioids or to morphine in low doses.

Nalbuphine and butorphanol are only available for parenteral administration which means that their usefulness in the treatment of chronic pain is limited. Meptazinol is restricted by its manufacturers to ‘short term’ treatment and there is little information on its use in chronic pain patients.     

Low ceiling respiratory depression by ciramadol

Ciramadol, an agonist-antagonist analgesic of lesser milligram potency than morphine, given intravenously at 30 mg/70 kg produced respiratory depression equivalent to that observed with morphine 10 mg/70 kg. Respiratory depression was measured in terms of drug induced displacement of the carbon dioxide response curve of healthy volunteers. In contrast to the progressive respiratory depression by each 10 mg/70 kg increment of morphine, further doses of ciramadol up to 90 mg/70 kg failed to increase respiratory depression. The ceiling of respiratory depression by ciramadol was half the ceiling previously demonstrated for nalbuphine and dezocine. Ceiling respiratory depression may be a general characteristic of agonist-antagonist type analgesics in contrast to pure agonist analgesics.     

Simple methodology of assessment of analgesics' addictive potential in mice.

Comparative investigation of analgesic (writhing test) and reinforcing (conditioned place preference) effects of 11 opioids over a wide range of doses was performed in mice. On the basis of the dose-response curves analysis, parameters of potency and efficacy of the reinforcing effect were determined. In one group of analgesics (etorphine, fentanyl, buprenorphine, morphine, promedol) ED50 in both tests were approximately equal. The other compounds (pentazocine, nalbuphine, nalorphine, butorphanol, U50,488H) demonstrated dissociation of two effects. The new indices (addictive index and safety index) for the prediction of analgesics' as well as other psychotropic drugs' abuse potential at the preclinical stage of their study have been suggested.     

Pharmacological profile of the potentiation of opioid analgesia by restraint stress

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.     

Influence of gonadectomy on the antinociceptive effects of opioids in male and female rats

RATIONALE: Sex differences in the antinociceptive effects of opioids have been reported in a variety of nociceptive assays, and it has been postulated that these differences are mediated by gonadal hormones. OBJECTIVES: The present study examined the influence of gonadectomy on opioid antinociception in male and female rats. METHODS: In a warm-water, tail-withdrawal procedure, the antinociceptive effects of the high-efficacy micro opioids etorphine and morphine; the low-efficacy micro opioids buprenorphine and dezocine; and the low-efficacy, mixed-action opioids butorphanol and nalbuphine were examined in intact and gonadectomized rats of the F344 and Sprague Dawley (SD) strains. RESULTS: The opioids examined were generally more potent in producing an antinociceptive effect in intact males than intact females, with larger sex differences observed with the less-effective opioids. In F344 males, gonadectomy produced small decreases in the potency of etorphine and morphine, and large decreases in the potency of buprenorphine, dezocine, butorphanol, and nalbuphine. Similar effects were obtained in SD males, with gonadectomy decreasing the potency of each of the opioids tested. In F344 females, gonadectomy produced small increases in the potency of etorphine and large increases in the potency of buprenorphine, dezocine, butorphanol, and nalbuphine. A similar effect was obtained in SD females, as gonadectomy increased the potency of etorphine, morphine, and buprenorphine. In both sexes, gonadectomy had a greater effect in F344 than SD rats. CONCLUSIONS: These findings suggest that gonadectomy decreases opioid antinociception in male rats and increases opioid antinociception in female rats. Additionally, the influence of gonadectomy on opioid antinociception appears to be determined by the relative effectiveness of the opioid tested and the rodent strain used.     

2013-2015年重庆地区39家医院阿片类止痛药利用分析

目的:为阿片类止痛药的生产、使用及监管提供参考。方法:对重庆地区39家医院2013-2015年阿片类止痛药物的销售金额、用药频度(DDDs)、限定日费用(DDC)和排序比进行统计分析。结果:重庆地区阿片类止痛药销售总金额2014年较2013年增长12.9%;2015年较2014年增长16.6%。销售金额前5位的药品分别为地佐辛注射液、盐酸吗啡缓释片、盐酸羟考酮缓释片、芬太尼透皮贴剂以及喷他佐辛注射剂。DDDs前5位的药品分别为枸橼酸芬太尼注射剂、盐酸吗啡缓释片、芬太尼透皮贴剂、盐酸羟考酮缓释片以及盐酸吗啡注射剂。DDC前5位的药品分别为地佐辛注射剂、喷他佐辛注射剂、盐酸羟考酮注射剂、酒石酸布托啡诺注射剂、酒石酸布托啡诺鼻喷剂。销售金额前10位药品中,地佐辛注射液、盐酸羟考酮缓释片、喷他佐辛注射剂、布托啡诺注射液、羟考酮注射液排序比小于1。结论:重庆地区阿片类止痛药销售总金额呈逐年增长趋势,品种结构基本合理,但对重点关注品种,尤其是地佐辛、喷他佐辛等销售金额大,DDC偏高,排序比明显偏低的品种,仍需加强合理用药监管力度。     

Depression of hepatic glutathione by opioid analgesic drugs in mice

The ability of morphine and other opioid analgesic drugs to diminish hepatocellular glutathione (GSH) concentrations was examined in ICR mice. When administered intraperitoneally, morphine, hydromorphone, ethylmorphine, l-alpha-acetylmethadol (LAAM), and meperidine all caused a significant decrease in hepatic GSH concentrations in male mice while codeine, methadone, butorphanol, nalbuphine, and pentazocine were without effect even at doses up to those approaching acute lethality. Depression of hepatic GSH equivalent to that observed after ip administration could be elicited by icv administration of small doses of morphine, ethylmorphine, and hydromorphone. LAAM and meperidine were ineffective following icv administration in these experiments. The discrepancy between results following ip versus icv administration of LAAM and meperidine suggests that hepatic metabolism of some opioids may be important for their activity in the CNS, as both norLAAM and normeperidine diminished hepatic GSH when administered by the icv route. The opioid-induced lowering of hepatic GSH does not appear to be sex-dependent since morphine and LAAM produced qualitatively and quantitatively similar effects on hepatic GSH in female mice. Morphine administered icv produced a substantial increase in the hepatotoxicity of two compounds dependent upon GSH for detoxification, acetaminophen and cocaine, as measured by serum alanine aminotransferase activities. These observations indicate that a number of opioid analgesic drugs have the potential to diminish hepatic GSH. Further, these results support earlier studies which indicate that central opioid effects on hepatic GSH are mediated through mu-opioid receptor stimulation. Last, these studies suggest that a centrally initiated opioid action on hepatic GSH may significantly influence the susceptibility of the liver to the effects of some hepatotoxic agents.     

Which potent opioid? Important criteria for selection

Opioids remain the drugs of choice for the treatment of severe pain. In recent years several new potent opioids have become available for clinical use. These newer drugs are generally safer than the older morphine-like compounds and their differing pharmacological and pharmacokinetic properties allow the physician to choose an appropriate drug according to the clinical situation and need of an individual patient. These drugs are classified according to their activity at the opioid receptors. The opioid agonists produce their pharmacological effect by an almost exclusive action at mu-receptors. The agonist-antagonist group are kappa-receptor agonists and either competitive antagonists at the mu-receptor or weak mu-agonists. The use of the potent opioid agonists, because of their potential for causing respiratory depression, is restricted to hospitals. Fentanyl, the oldest drug of this class, is extensively used as a supplement to general anaesthesia, or in high doses as a 'complete' anaesthetic for patients undergoing cardiac surgery. Alfentanil and sufentanil are newer fentanyl derivatives. Alfentanil is unique in having a very short elimination half-life. This is a particular advantage during short operations and for day-case surgery. For longer operations alfentanil can be given as a continuous infusion to supplement nitrous oxide anaesthesia. Sufentanil is about 10 times more potent than fentanyl and is more rapidly eliminated. Initial reports suggest that it may be more effective than fentanyl as an anaesthetic supplement and that recovery may be more rapid. Both sufentanil and alfentanil are also used in cardiac anaesthesia. The newer agonist-antagonist opioids, butorphanol, nalbuphine and buprenorphine, have largely replaced pentazocine in clinical practice. Unlike pentazocine, they cause a low incidence of dysphoric side effects. Like the pure agonists, they cause respiratory depression; however, in contrast to the pure agonists this is not dose related, reaching a 'ceiling' as dose increases. The risk of dependence is also less, so that these drugs are safer for the treatment of chronic pain. Additionally, it is particularly worth noting that buprenorphine and nalbuphine cause minimal cardiovascular changes, and are safe and effective drugs for treatment of pain associated with myocardial infarction. Buprenorphine, which is effective parenterally, orally and sublingually, has a prolonged duration of action (up to 12 hours after a single dose).     

Sex-related differences in the antinociceptive effects of opioids: importance of rat genotype, nociceptive stimulus intensity, and efficacy at the µ opioid receptor

RATIONALE: Recent studies indicate that morphine is more potent as an antinociceptive agent in male than female rodents and monkeys. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Age-related differences in sensitivity to the antinociceptive effects of opioids in male rats. Influence of nociceptive intensity and intrinsic efficacy at the mu receptor

RATIONALE: Despite the widespread popularity of opioid analgesics, significant differences in the potency and effectiveness of these drugs are often observed across age groups. OBJECTIVES: The purpose of this investigation was to examine age-related differences in sensitivity to the antinociceptive effects of mu opioids and to identify the conditions under which these differences are most apparent. METHODS: In a warm-water tail-withdrawal procedure, young (3 months) and aged (24 months) male rats were habituated to restraint and the latencies to remove their tails from 50 degrees C (low nociceptive intensity) and 55 degrees C (high nociceptive intensity) water were measured. Opioids possessing a range of intrinsic efficacy at the mu receptor (morphine, levorphanol, buprenorphine, butorphanol, nalbuphine, nalorphine) were examined. RESULTS: Young and aged rats were equally sensitive to the antinociceptive effects of morphine, levorphanol, and buprenorphine when tested at the low nociceptive intensity. When these drugs were tested at the high nociceptive intensity, differences between the two age groups became apparent, such that aged rats were significantly more sensitive to the antinociceptive effects of these drugs than young rats. Differences between age groups were most apparent when butorphanol, nalbuphine, and nalorphine were tested, in that each of these drugs produced maximal levels of antinociception in aged rats under conditions in which they failed to produce antinociceptive activity in young rats. Under conditions in which lower efficacy opioids failed to produce antinociceptive activity in young rats, they antagonized the effects of morphine in drug combination tests. CONCLUSIONS: These data may be taken as evidence that aged male rats are more sensitive to the antinociceptive effects of mu opioids than young male rats, and that age-related differences in opioid sensitivity are most apparent when lower efficacy opioids and higher nociceptive intensities are employed during behavioral testing.     

Uniform assessment and ranking of opioid μ receptor binding constants for selected opioid drugs

The safe disposal of unused opioid drugs is an area of regulatory concern. While toilet flushing is recommended for some drugs to prevent accidental exposure, there is a need for data that can support a more consistent disposal policy based on an assessment of relative risk. For drugs acting at the Mu-opioid receptor (MOR), published measurements of binding affinity (K(i)) are incomplete and inconsistent due to differences in methodology and assay system, leading to a wide range of values for the same drug thus precluding a simple and meaningful relative ranking of drug potency. Experiments were conducted to obtain K(i)'s for 19 approved opioid drugs using a single binding assay in a cell membrane preparation expressing recombinant human MOR. The K(i) values obtained ranged from 0.1380 nM (sufentanil) to 12.486 μM (tramadol). The drugs were separated into three categories based upon their K(i) values: K(i) > 100 nM (tramadol, codeine, meperidine, propoxyphene and pentazocine), K(i)=1-100 nM (hydrocodone, oxycodone, diphenoxylate, alfentanil, methadone, nalbuphine, fentanyl and morphine) and K(i) < 1 nM (butorphanol, levorphanol, oxymorphone, hydromorphone, buprenorphine and sufentanil). These data add to the understanding of the pharmacology of opioid drugs and support the development of a more consistent labeling policies regarding safe disposal.