Broad analgesic profile of buprenorphine in rodent models of acute and chronic pain

Buprenorphine is a potent opioid analgesic clinically used to treat moderate to severe pain. The present study assessed its analgesic efficacy in a broad range of rodent models of acute and chronic pain. In the phenylquinone writhing, hot plate, and tail flick mouse models of acute pain, full analgesic efficacy was obtained (ED50 values: 0.0084-0.16 mg/kg i.v.). Full analgesic efficacy was also obtained in yeast- and formalin-induced inflammatory pain (ED50 values: 0.0024-0.025 mg/kg i.v., rats and mice) and in mustard-oil-induced spontaneous pain, referred allodynia, and referred hyperalgesia in mice (ED50 values: 0.018-0.025 mg/kg i.v.). Buprenorphine strongly inhibited mechanical and cold allodynia in mononeuropathic rats, as well as mechanical hyperalgesia and cold allodynia in polyneuropathic rats (ED50 values: 0.055 and 0.036 mg/kg i.v. and 0.129 and 0.038 mg/kg i.p., respectively). It is concluded that buprenorphine shows a broad analgesic profile and offers the opportunity to treat different pain conditions, including neuropathic pain.     

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.     

The problem of pain: Additive analgesic effect of tramadol and buprenorphine in a patient with opioid use disorder

Background: There is a paucity of published literature on the optimal treatment of pain in patients on buprenorphine treatment (BT) for opioid use disorder. Using this case report, we hope to demonstrate that tramadol may represent an effective treatment option for pain in patients on BT while encouraging future clinical trials. Case: The patient is a 56-year-old Caucasian male with a history of opiate use disorder on treatment with buprenorphine/naloxone 8/2?mg 2 times a day (BID) who was followed in an outpatient general psychiatry clinic that specializes in patients with co-occurring substance use disorders. Although maintaining sobriety from opioids, the patient continued to struggle with acute on chronic pain secondary to osteoarthritis that had left him walking with a cane. The patient was started on tramadol 50?mg 3 times a day (TID) for acute pain by his primary care physician (PCP) while he awaited surgical intervention. He reported analgesic effect with buprenorphine/naloxone but noted that it did not last the full period between his doses. He reported further improvement in his pain along with greater daily functioning with the additional use of tramadol, without side effects or withdrawal symptoms. Discussion: Current recommendations for pain management in patients on BT include discontinuation of BT therapy and/or addition of an adjunctive opioid analgesic (including additional buprenorphine/naloxone) while continuing agonist medication for treatment of opioid use disorder. However, determining which medication to use can be difficult, as there has been no literature examining this issue. In this case, the combination of buprenorphine and tramadol demonstrated an additive analgesic effect. Randomized control studies need to be performed to further understand the changes in pain measurement in patients on BT with tramadol compared with other adjunctive analgesic medications.     

Analgesic synergism between intrathecal morphine and cyclooxygenase-2 inhibitors in mice

The analgesic effects of the intrathecal coadministration of morphine with nimesulide, meloxicam and parecoxib, preferential cyclooxygenase-2 (COX-2) inhibitors, were studied in mice using a chemical model of visceral pain, the acetic acid writhing test. Isobolographic analysis was used to characterize the interactions between mixtures of morphine with each non-steroidal anti-inflammatory drug. Antinociception dose-response curves were analyzed to obtain the ED50's of each drug. A dose response curve for fixed ratio mixtures of morphine with COX-2 inhibitors was then performed and the observed ED50's were plotted on a two-dimensional isobologram. All the combinations tested showed synergistic interactions and the strength of the interaction was ranked as: morphine/parecoxib>morphine/meloxicam>morphine nimesulide. The results demonstrate that the intrathecal coadministration of COX-2 inhibitors significantly enhance morphine-induced antinociception and could result in an opioid sparing action which may be useful in the clinical treatment of severe pain. A sparing action means that less opioids have to be administered to obtain a given analgesic effect. Since intrathecal morphine is often used in clinical pain situations, the opioid sparing effect resulting from the synergy observed with the coadministration of COX-2 inhibitors may be clinically relevant. One of the most significant advantages should be the reduction of opioid toxicity which often acts as a major obstacle in pain treatment.     

Tramadol has a better potency ratio relative to morphine in neuropathic than in nociceptive pain models

BACKGROUND AND OBJECTIVE: Treatment of neuropathic pain remains a challenge and the role of various analgesics in this setting is still debated. The effects of tramadol, an atypically acting analgesic with a combined opioid and monoaminergic mechanism of action, and morphine, a prototypical opioid, were tested in rat models of neuropathic and nociceptive pain. METHODS: Cold allodynia and mechanical hypersensitivity, symptoms of neuropathic pain, were studied in rat models of mononeuropathic pain. Cold allodynia was analyzed in the chronic constriction injury (CCI) model and mechanical hypersensitivity was analyzed in the spinal nerve ligation (SNL) model. Heat-induced rat tail-flick latencies were determined as measure for nociceptive pain. RESULTS: Cold allodynia and mechanical hypersensitivity were strongly attenuated with similar absolute potency after intravenous administration of tramadol and morphine. The doses of drug that were calculated to result in 50% pain inhibition (ED(50)) for tramadol and morphine were 2.1 and 0.9 mg/kg, respectively, in CCI rats and 4.3 and 3.7 mg/kg, respectively, in SNL rats. In the tail-flick assay of acute nociception, the potency of the two drugs differed markedly, as seen by ED(50) values of 5.5 and 0.7 mg/kg intravenously for tramadol and morphine, respectively. Accordingly, the analgesic potency ratio (ED(50) tramadol/ED(50) morphine) of both compounds differed in neuropathic (potency ratio 2.3 in CCI and 1.2 in SNL) and nociceptive pain models (potency ratio 7.8), suggesting a relative increase in potency of tramadol in neuropathic pain compared with nociceptive pain. CONCLUSION: The results of this study are consistent with clinical data supporting the efficacy of opioids in neuropathic pain conditions, and furthermore suggest an additional contribution of the monoaminergic mechanism of tramadol in the treatment of neuropathic pain states.     

CB1 and CB2 receptor agonists promote analgesia through synergy in a murine model of tumor pain

In light of the adverse side-effects of opioids, cannabinoid receptor agonists may provide an effective alternative for the treatment of cancer pain. This study examined the potency and efficacy of synthetic CB1 and CB2 receptor agonists in a murine model of tumor pain. Intraplantar injection of the CB1 receptor agonist arachidonylcyclopropylamide (ED(50) of 18.4 μg) reduced tumor-related mechanical hyperalgesia by activation of peripheral CB1 but not CB2 receptors. Similar injection of the CB2 receptor agonist AM1241 (ED50 of 19.5 μg) reduced mechanical hyperalgesia by activation of peripheral CB2 but not CB1 receptors. Both agonists had an efficacy comparable with that of morphine (intraplantar), but their analgesic effects were independent of opioid receptors. Isobolographic analysis of the coinjection of arachidonylcyclopropylamide and AM1241 determined that the CB1 and CB2 receptor agonists interacted synergistically to reduce mechanical hyperalgesia in the tumor-bearing paw. These data extend our previous findings that the peripheral cannabinoid receptors are a promising target for the management of cancer pain and mixed cannabinoid receptor agonists may have a therapeutic advantage over selective agonists.     

Importance of sex and relative efficacy at the µ opioid receptor in the development of tolerance and cross-tolerance to the antinociceptive effects of opioids

RATIONALE: Recent studies indicate that mu opioids are generally more potent and effective as antinociceptive agents in male than female rodents. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Continuous-plus-on-demand epidural infusion of buprenorphine versus morphine in postoperative treatment of pain. Postoperative epidural infusion of buprenorphine

In a randomized, double-blind study, buprenorphine was compared with morphine in the treatment of pain after major abdominal operations by means of continuous-plus-on-demand epidural infusion for constant analgesia. The patients received bolus epidural injections of 0.15 mg buprenorphine or 2 mg morphine-HCl prior to an on-demand epidural infusion of 0.03% buprenorphine or 0.25% morphine HCl at a basal rate of 0.06 ml/h. Over 50 h, mean buprenorphine consumption was 0.85 +/- 0.08 mg, and mean morphine consumption was 6.4 +/- 0.5 mg. Under the treatment, no discomfort or side-effects necessitating treatment occurred. We conclude that buprenorphine is a useful substitute for morphine in the treatment of pain after major abdominal operations by continuous-plus-on-demand epidural infusion, and that the relative analgesic potency ratio of epidural buprenorphine is 8.     

Buprenorphine 5, 10 and 20 μg/h transdermal patch: a review of its use in the management of chronic non-malignant pain

This article reviews the pharmacology, therapeutic efficacy and tolerability profile of the 7-day lower-dose (5, 10 and 20?μg/h) buprenorphine transdermal patch (BuTrans?, Norspan?) in the management of chronic non-malignant pain, with a focus on European labelling for the drug. Buprenorphine is a semi-synthetic opioid analgesic that acts primarily as a partial agonist at the mu opioid receptor. The transdermal formulation provides continuous delivery of buprenorphine, resulting in relatively consistent plasma drug concentrations throughout the 7-day dosing interval. The analgesic efficacy of transdermal buprenorphine in patients with osteoarthritis of the hip and/or knee has been demonstrated in several randomized controlled trials, which have shown the formulation to be equivalent to sublingual buprenorphine, noninferior to prolonged-release tramadol tablets, noninferior to codeine plus paracetamol (acetaminophen) combination tablets (when transdermal buprenorphine was used together with regularly scheduled oral paracetamol) and generally superior to a matching transdermal placebo patch. Transdermal buprenorphine was significantly more effective than placebo in reducing chronic low back pain of at least moderate severity in two randomized, double-blind, crossover trials. Other clinical trials, including a randomized, double-blind, maintenance-of-analgesia study, have also demonstrated the analgesic efficacy of transdermal buprenorphine in patients with chronic non-malignant pain of various causes. In general, serious adverse events with transdermal buprenorphine are similar to those for other opioid analgesics. Transdermal buprenorphine has a ceiling effect for respiratory depression, and the main risk is when it is combined with other CNS depressants. The most frequently reported adverse events with transdermal buprenorphine are headache, dizziness, somnolence, constipation, dry mouth, nausea, vomiting, pruritus, erythema, application site pruritus and application site reactions. Transdermal buprenorphine was better tolerated than sublingual buprenorphine in a 7-week, randomized, double-blind trial in patients with osteoarthritis pain. Nevertheless, as with other opioids, persistence with transdermal buprenorphine therapy is difficult for many patients because of adverse events or other reasons. Thus, transdermal buprenorphine has generally demonstrated good efficacy and tolerability in clinical trials in chronic non-malignant pain, providing effective background analgesia as part of pain management strategies for patients with osteoarthritis, low back pain and other persistent pain syndromes of at least moderate severity. It also has favourable pharmacodynamic and pharmacokinetic properties, which have beneficial clinical implications, most notably the convenience of once-weekly administration and no need for dosage adjustments in the elderly or those with compromised renal function, making it an opioid of choice in these patients, and a useful therapeutic option overall in the management of chronic non-malignant pain.     

Transdermal buprenorphine

Buprenorphine is a low molecular weight, lipophilic, opioid analgesic. Recently, a transdermal matrix patch formulation of buprenorphine has become available in three dosage strengths designed to release buprenorphine at 35, 52.5 and 70 micro g/h over a 72-hour period. At least satisfactory analgesia with minimal requirement for rescue medication (50% of patients treated with transdermal buprenorphine, in two trials. Furthermore, despite the availability of rescue medication to all patients, those receiving transdermal buprenorphine tended to experience greater pain relief, reduced pain intensity and longer pain-free sleep. Transdermal buprenorphine was generally well tolerated. Systemic adverse events were typical of opioid treatment or were attributable to the underlying disease.     

The role of descending fibers from the rostral ventromedial medulla in opioid analgesia in rats

There has been controversy as to whether the contribution of descending fibers from the rostral ventromedial medulla to opioid analgesia depends on the nature of the noxious stimulus eliciting pain. In the present study, inactivation of descending fibers by microinjection of muscimol (50 ng) in the rostral ventromedial medulla abolished morphine analgesia in the tail immersion and hot plate tests but decreased morphine analgesia by 60% in the formalin test. Analysis of the dose-response relation for morphine after inactivation of descending fibers revealed that, except for the tail immersion test, high doses of morphine could not overcome the block induced by muscimol. Also, morphine analgesia elicited supraspinally was not detectable when descending fibers were inactivated, suggesting that the analgesic effect of morphine in the brain requires a relay via the rostral ventromedial medulla. The analgesic effect of buprenorphine also depends on the integrity of descending fibers from the rostral ventromedial medulla. The results indicate that descending fibers from the rostral ventromedial medulla are critically important to the analgesic effect of opioids, regardless of the type of noxious stimulation eliciting pain. Residual analgesic effects of opioids after inactivation of descending fibers may be due to peripheral effects in the presence of inflammation.     

Intrathecal injection of codeine, buprenorphine, tilidine, tramadol and nefopam depresses the tail-flick response in rats

The effect of intrathecal (i.t.) injection of the analgesic agents, codeine, buprenorphine, tilidine and one of its metabolites, nortilidine, tramadol and nefopam, was determined in the tail-flick test performed on rats. ED50 values were derived from the dose-response lines. The relative potency ranking established from the ED50 values is buprenorphine (0.4 nM) greater than nortilidine (29 nM) = tramadol (26 nM) = nefopam (34 nM) greater than codeine (42 nM) greater than tilidine (118 nM). An i.t. injection of the opiate antagonist, naloxone (5 micrograms), prevented the antinociceptive effect of all analgesic agents administered at the highest dose tested. It is concluded that these analgesic agents, like morphine, exert their effect at least in part through a spinal site of action.     

Analgesic synergy between topical opioids and topical non-steroidal anti-inflammatory drugs in the mouse model of thermal pain

The main aim of the study was to examine analgesic effects of the topical opioids and non-steroidal anti-inflammatory drugs (NSAIDs) in a radiant heat tail-flick nociception model. Also, we have tested whether the addition of lauric acid to propylene glycol improves skin permeation for the opioids and NSAIDs. We found that the addition of lauric acid to propylene glycol dramatically improves the penetration of the drugs, measured by the drug's ED(50). We observed a significant dose response shift to the left for all tested drugs. So, morphine's ED(50) was decreased by 19-fold. The duration of the analgesic activity of morphine dissolved in a combination of propylene glycol and lauric acid was much longer compared with the same dose of the drug dissolved in propylene glycol only. Methadone and hydrocodone also produced analgesic activity in this experimental paradigm. We then assessed potential interactions between opioids, ibuprofen and diclofenac using a fixed, low dose of each. The inclusion of either S-ibuprofen or diclofenac to a fixed, low dose of morphine raised the analgesic response from around 20% to 50% and 80%, respectively. Topical methadone and diclofenac alone produced analgesia in 30% of mice. The combination produced analgesia in 100% of mice (100% versus 60%, P<0.001) and the analgesic effect was observed for 90 min. Alone, topical methadone and S-ibuprofen produced analgesia in 25% and 30% of mice, respectively. The combination elicited analgesia in 100% of mice (100% versus 55%, P<0.001) and this analgesic effect lasted for 120 min. Our current findings support the supra-additive interaction of topical mu opioids, S-ibuprofen and diclofenac in a model of moderate to severe pain, radiant heat tail-flick assay.     

丁丙诺啡用于妇科术后镇痛

双盲试验40例随机分为4组,分别肌注丁丙诺啡0.3mg、0.15mg、哌替啶50mg和安慰剂;开放试验30例,只给予丁丙诺啡0.3mg。结果表明,两种设计的丁丙诺啡镇痛强度都明显高于安慰剂(P<0.01)。双盲法丁丙诺啡0.15mg具有和哌替啶50mg相同的镇痛作用,丁丙诺啡0.3mg则在给药3h后镇痛作用优于哌替啶(P<0.05);镇痛作用持续时间均超过6h。     

Analgesic responses elicited by endogenous enkephalins (protected by mixed peptidase inhibitors) in a variety of morphine-sensitive noxious tests

It has been suggested that the endogenous opioid peptides, methionine and leucine enkephalin, participate only in naloxone-facilitated antinociceptive responses. To reassess this proposal, analgesic effects resulting from complete inhibition of enkephalin metabolism by intracerebroventricular (i.c.v.) administration of the mixed inhibitor RB 38A (R,S)HONHCOCH2CH(CH2 phi)CONHCH(CH2 phi)COOH) were compared to the effects of morphine (i.c.v.) in various assays commonly used to select analgesics: mouse hot plate-test, tail flick test with mice and rats, electrical stimulation of the tail (TES), paw pressure test with rats, and phenylbenzoquinone-induced writhing test with mice. The ED50s of morphine vs. ED50s of RB 38A in the writhing, hot plate (jumping) and tail flick tests with mice were 0.24 nmol vs. 38 nmol, 1 nmol vs. 36 nmol and 3.2 nmol vs. 285 nmol, respectively. RB 38A (ED30 153 nmol) was only 15 times less active in the tail flick test with rats than morphine and only halve as active in the paw pressure test. Noxious TES in rat was very sensitive to the inhibitory action of endogenous opioids protected by RB 38A, particularly the post-vocalization response which was also shown to be alleviated by antidepressants. All the analgesic effects observed were reversed by naloxone. This first direct evidence of analgesia resulting from peptidase inhibition, in the tail flick test with mice and rats, hot plate (paw lick) and TES shows that the pain suppressive effects of endogenous opioid peptides are not restricted to naloxone-facilitated noxious stimuli but occur more generally, in all morphine-sensitive tests. The differential effects of RB 38A in the various assays is likely to be related to the amount of enkephalins released and to the efficiency of peptidase inactivation in particular brain regions implicated in the control of a given nociceptive input. This mechanism could account for the reduction in side-effects compared to those of morphine following chronic administration of RB 38A.     

Pharmacological interaction of opiates with various classes of centrally acting dopaminergic drugs.

The comparative analgesic and sedative (narcosis potentiating) efficacy of mu and kappa opioids was studied as a function of time in rats and mice. The mu agonists, morphine and fentanyl, produced antinociceptive actions against both heat and chemical noxious agents, but the half-lives of their ED50s were longer in the writhing than in the hot plate test. The kappa agonist drugs, bremazocine, ethylketocyclazocine and pentazocine, proved to be inactive against heat nociception, and produced a potent, long-lasting analgesia in the acetic acid writhing test, similar to mu agonists. The combination of two mu agonists resulted in a synergistic interaction and a remarkable prolongation of antinociceptive action. When the kappa-drug bremazocine was coadministered with morphine, there was a significant prolongation of the duration of analgesic action, without any influence on the potency. The interactions of mu and kappa opioids with agonists and antagonists at dopamine receptors were also studied in narcosis. The time course of the naloxone-morphine antagonism in analgesiometric assays revealed similarities, when apparent pA2 values were estimated at the peak of agonist and antagonist activity, but it was different in the writhing test when the pA2 was determined 84 minutes after morphine administration (EDt1/2, half-life belonging to the ED50) while naloxone was given at its peak effect.     

Buprenorphine 5, 10 and 20 μg/h transdermal patch: a guide to its use in chronic non-malignant pain

Buprenorphine lower-dose (5, 10 and 20?μg/h) transdermal patches, which are administered once every 7 days, are indicated in the management of chronic non-malignant pain. This review focuses on the labelling of this formulation (BuTrans?) in the EU. The analgesic efficacy of transdermal buprenorphine in patients with osteoarthritis of the hip and/or knee has been demonstrated to be equivalent to sublingual buprenorphine, noninferior to prolonged-release tramadol and generally superior to a matching transdermal placebo patch. When used together with regularly scheduled oral paracetamol (acetaminophen), transdermal buprenorphine was noninferior to codeine plus paracetamol. Transdermal buprenorphine has also shown analgesic efficacy in patients with chronic non-malignant pain of various causes.     

Cross-tolerance and mu agonist efficacy in pigeons treated with LAAM or buprenorphine

The mechanism responsible for decreased opioid use during opioid substitution therapy is not fully understood. To examine whether l-alpha-acetylmethadol (LAAM) or buprenorphine attenuate behavioral effects of opioids through cross-tolerance, discriminative stimulus effects of high and low efficacy mu agonists were examined following 3- or 7-day treatment with LAAM or buprenorphine in pigeons discriminating between saline and heroin or between saline and buprenorphine, respectively. Heroin, buprenorphine and nalbuphine occasioned high levels of drug-appropriate responding in both groups; kappa opioids and non-opioids occasioned predominantly saline-appropriate responding. Administration of LAAM (3.2 mg/kg) or buprenorphine (3.2 mg/kg) occasioned predominantly heroin- or buprenorphine-appropriate responding, respectively. After discontinuation of LAAM treatment, the potency in occasioning heroin-key responding was markedly decreased for nalbuphine, slightly decreased for buprenorphine, and unchanged for heroin. Following discontinuation of buprenorphine treatment, the potency in occasioning buprenorphine-key responding was decreased for nalbuphine and unchanged for buprenorphine and heroin. Thus, greater cross-tolerance developed from LAAM and buprenorphine to low efficacy mu agonists as compared to a higher efficacy agonist. Failure of LAAM and buprenorphine treatment to modify the effects of heroin, under conditions that attenuate the effects of lower efficacy mu opioids, provides a possible rationale for why heroin abuse persists in some patients receiving large doses of agonists in substitution therapy.     

Tramadol as an analgesic for mild to moderate cancer pain

In most cancer patients, pain is successfully treated with pharmacological measures such as opioid analgesics alone or opioid analgesics combined with adjuvant analgesics (co-analgesics). Opioids for mild-to-moderate pain (formerly called weak opioids) are usually recommended in the treatment of cancer pain of moderate intensity. There is a debate whether the second step of the WHO analgesic ladder, which, in Poland, is composed of opioids such as tramadol, codeine, dihydrocodeine (DHC), is still needed for cancer pain treatment. One of the most interesting and useful drugs in this group is tramadol. Its unique mechanism of action, analgesic efficacy and profile of adverse effects are responsible for its successful use in patients with different types of acute and chronic pain, including neuropathic pain. The aim of this article is to summarize the data regarding pharmacodynamics, pharmacokinetics, possible drug interactions, adverse effects, dosing guidelines, equipotency with other opioid analgesics and clinical studies comparing efficacy, adverse reactions and safety of tramadol to other opioids in cancer pain treatment.