buprenorphine and Neuralgia

The objective of this systematic review is to present the available evidence for the utilization of the atypical opioids tapentadol, buprenorphine, and levorphanol for the treatment of neuropathic pain.. In total, 1619 articles were retrieved of which 10 studies were included. Of 5 included studies pertaining to tapentadol, 4 studies show tapentadol monotherapy to be effective for the treatment of diabetic peripheral neuropathy or chronic, radiating low back pain. Of the 3 studies included for buprenorphine, only one was a randomized controlled trial found not to have a statistically significant reduction in pain with TD buprenorphine likely due to very high withdrawal rates during the trial. Only 2 case reports were included from the available literature for levorphanol providing low-quality anecdotal evidence. The role of tapentadol, buprenorphine, and levorphanol for neuropathic pain conditions requires robust research including randomized controlled trials to evaluate their efficacy and safety.

Topics: Analgesics, Opioid; Buprenorphine; Humans; Levorphanol; Neuralgia; Randomized Controlled Trials as Topic; Tapentadol; Treatment Outcome

Chronic pain, including neuropathic pain, represents an untreated disease with important repercussions on the quality of life and huge costs on the national health system. It is well known that opioids are the most powerful analgesic drugs, but they represent the second or third line in neuropathic pain, that remain difficult to manage. Moreover, these drugs show several side effects that limit their use. In addition, opioids possess addictive properties that are associated with misuse and drug abuse. Among available opioids compounds, buprenorphine has been suggested advantageous for a series of clinical reasons, including the effectiveness in neuropathic pain. Some properties are partly explained by its unique pharmacological characteristics. However, questions on the dynamic profile remain to be answered. Pharmacokinetics optimization strategies, and additional potentialities, are still to be explored. In this paper, we attempt to conceptualize the potential undiscovered dynamic profile of buprenorphine.

Topics: Analgesics; Buprenorphine; Chronic Pain; Humans; Neuralgia; Quality of Life

Opioid drugs, including buprenorphine, are commonly used to treat neuropathic pain, and are considered effective by some professionals. Most reviews have examined all opioids together. This review sought evidence specifically for buprenorphine, at any dose, and by any route of administration. Other opioids are considered in separate reviews.. To assess the analgesic efficacy of buprenorphine for chronic neuropathic pain in adults, and the adverse events associated with its use in clinical trials.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE from inception to 11 June 2015, together with reference lists of retrieved papers and reviews, and two online study registries.. We included randomised, double-blind studies of two weeks' duration or longer, comparing any oral dose or formulation of buprenorphine with placebo or another active treatment in chronic neuropathic pain.. Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality. We did not carry out any pooled analyses.. Searches identified 10 published studies, and one study with results in ClinicalTrials.gov. None of these 11 studies satisfied our inclusion criteria, and so we included no studies in the review.. There was insufficient evidence to support or refute the suggestion that buprenorphine has any efficacy in any neuropathic pain condition.

Topics: Adult; Analgesics, Opioid; Buprenorphine; Humans; Neuralgia

Neuropathic pain occurs in 1% of the population and is difficult to manage. Responses to single drugs are limited in benefit. Thirty percent will fail to respond altogether. This is a review of newer drugs and treatment paradigms.. A literature review was performed pertinent to new drugs and treatment algorithms in the management of neuropathic pain.. New information on opioids (tramadol and buprenorphine) suggests benefits in the management of neuropathic pain and has increased interest in their use earlier in the course of illness. Newer antidepressants, selective noradrenaline, and serotonin reuptake inhibitors (SNRIs) have evidence for benefit and reduced toxicity without an economic disadvantage compared to tricyclic antidepressants (TCAs). Pregabalin and gabapentin are effective in diabetic neuropathy and postherpetic neuralgia. Treatment paradigms are shifting from sequential single drug trials to multiple drug therapies. Evidence is needed to justify this change in treatment approach.. Drug choices are now based not only on efficacy but also toxicity and drug interactions. For this reason, SNRIs and gabapentin/pregabalin have become popular though efficacy is not better than TCAs. Multiple drug therapies becoming an emergent treatment paradigm research in multiple drug therapy are needed.

Topics: Buprenorphine; Drug Therapy, Combination; Humans; Narcotics; Neuralgia; Pain; Selective Serotonin Reuptake Inhibitors; Tramadol

To evaluate the efficacy and safety of transdermal buprenorphine in patients with diabetic peripheral neuropathic pain (DPNP).. This multicenter, randomized, double-blind, placebo-controlled, parallel-group trial enrolled patients with type 1 or type 2 diabetes and stable glycemic control who had been experiencing moderate to severe DPNP for at least 6 months on maximal tolerated conventional therapy. Patients were randomly assigned to receive buprenorphine (5 μg/h) or placebo patches. The dose was titrated to effect to a maximum of 40 μg/h. Paracetamol was available as rescue analgesia. The severity of pain and other symptoms of DPNP were assessed daily in a patient diary and at clinic visits.. One hundred eight-six patients were enrolled, with 93 randomized to either buprenorphine or placebo. A high proportion of patients did not complete the study (buprenorphine 37 of 93, placebo 24 of 93). The main reason for premature withdrawal in the buprenorphine group was adverse events commonly due to untreated nausea and/or vomiting. Among the per-protocol population, more patients in the buprenorphine group (86.3%) experienced a 30% reduction in average versus baseline pain at week 12 than those in the placebo group (56.6%, P < 0.001). A nonsignificant trend favored the buprenorphine group within the intention-to-treat analysis of the same end point (51.7% vs. 41.3%, P = 0.175).. Transdermal buprenorphine, when tolerated, is an effective therapy for DPNP and provides another option to manage this challenging painful condition. Nausea and constipation need to be managed proactively to optimize treatment outcomes.

Topics: Acetaminophen; Administration, Cutaneous; Adult; Aged; Analgesics, Non-Narcotic; Analgesics, Opioid; Buprenorphine; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Double-Blind Method; Female; Humans; Intention to Treat Analysis; Male; Middle Aged; Nausea; Neuralgia; Treatment Outcome; Vomiting; Withholding Treatment

This open-label, phase 3b study evaluated the effectiveness and tolerability of oral tapentadol prolonged release (PR; 50-250 mg twice daily [b.i.d.]) for managing severe, chronic low back pain in patients responding to World Health Organization (WHO) step III opioids but tolerating treatment poorly. Equianalgesic ratios for tapentadol to prior strong opioids were calculated.. Patients rotated directly from prior WHO step III opioids to tapentadol. Patients received tapentadol PR (50-250 mg b.i.d.) during 5-week titration and 7-week maintenance periods. Tapentadol immediate release (IR) 50 mg (≤ twice/day, ≥ 4 h apart) was allowed (total daily dose of tapentadol PR and IR ≤ 500 mg/day). The primary endpoint was responder rate 1 at week 6 (percentage of patients with the same or less pain intensity [11-point numerical rating scale (NRS; 3-day average)] vs week -1).. Responder rate 1 at week 6 (last observation carried forward [LOCF]) was 80.9% (76/94; P < 0.0001 vs. the null responder hypothesis rate [<60%]), resulting in a positive trial despite premature termination (136 recruited of 180 planned). Significant improvements from baseline in pain intensity and neuropathic pain symptoms were observed at weeks 6 and 12 with tapentadol PR (P < 0.05). Equianalgesic ratios were calculated for PR formulations alone and for PR and IR formulations combined for tapentadol to oxycodone, buprenorphine, fentanyl, morphine, and hydromorphone. The prevalences of adverse events reported as the reason for switching to tapentadol (most commonly constipation and nausea) decreased over time.. Tapentadol PR (50-250 mg b.i.d.) provided at least comparable pain relief and improved tolerability versus prior strong opioids in patients with severe, chronic low back pain responding to WHO step III therapy. Conversion from strong opioids to tapentadol PR, with its two mechanisms of action, went smoothly considering overall effectiveness and tolerability outcomes. Equianalgesic ratios of tapentadol to oxycodone and other strong opioids were in line with other phase 3/3b studies.

Topics: Adult; Aged; Analgesics, Opioid; Buprenorphine; Chronic Pain; Constipation; Delayed-Action Preparations; Female; Fentanyl; Humans; Hydromorphone; Low Back Pain; Male; Middle Aged; Morphine; Neuralgia; Oxycodone; Pain Measurement; Phenols; Severity of Illness Index; Tapentadol

Buprenorphine is a potent opioid available as a transdermal delivery system (TDS) formulation. This open-label study investigated its safety, tolerability, and efficacy in 30 patients with chronic painful neuropathy. Subjects with visual analogue scale (VAS) score > or = 5 under stable analgesic treatment were entered. The starting dosage of 35 microg/h was increased up to 70.0 microg/h in case of unsatisfactory pain control as assessed by fortnightly visits. The primary endpoint was the number of patients achieving at least 30% pain relief at day 42 visit. Treatment was safe over the study period. Nine patients dropped out for side effects, mostly nausea and daily sleepiness. Buprenorphine TDS was well tolerated in 21 patients. Thirteen patients achieved > 30% of pain relief at day 42 visit. Five patients needed to increase the dosage to 52.5 microg/h. Eight patients did not meet the primary outcome, but none allowed increasing the dosage to 70 microg/h, and four patients withdrew consent to continue the study before day 42 visit because of a 'fear to become addicted,' although 40% had obtained VAS reduction. In our study, which needs to be confirmed by a controlled trial, buprenorphine TDS induced clinically meaningful pain relief in about 40% of patients with chronic painful neuropathy, suggesting its use as a third-line treatment.

Topics: Administration, Cutaneous; Adult; Aged; Analgesics, Opioid; Buprenorphine; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Neuralgia; Pain Measurement; Peripheral Nervous System Diseases; Time

Topics: Analgesics; Analgesics, Opioid; Animals; Animals, Laboratory; Buprenorphine; Chemokines, C; Integrins; Mice; Morphine; Neuralgia; Peripheral Nerve Injuries; Receptors, Chemokine

Neuropathic pain is a serious clinical issue, and its treatment remains a challenge in contemporary medicine. Thus, dynamic development in the area of animal and clinical studies has been observed. The mechanisms of neuropathic pain are still not fully understood; therefore, studies investigating these mechanisms are extremely important. However, much evidence indicates that changes in the activation and infiltration of immune cells cause the release of pronociceptive cytokines and contribute to neuropathic pain development and maintenance. Moreover, these changes are associated with low efficacy of opioids used to treat neuropathy. To date, the role of CC chemokine receptor type 3 (CCR3) in nociception has not been studied. Similarly, little is known about its endogenous ligands (C-C motif ligand; CCL), namely, CCL5, CCL7, CCL11, CCL24, CCL26, and CCL28. Our research showed that the development of hypersensitivity in rats following chronic constriction injury (CCI) of the sciatic nerve is associated with upregulation of CCL7 and CCL11 in the spinal cord and dorsal root ganglia (DRG). Moreover, our results provide the first evidence that single and repeated intrathecal administration of the CCR3 antagonist SB328437 diminishes mechanical and thermal hypersensitivity. Additionally, repeated administration enhances the analgesic properties of morphine and buprenorphine following nerve injury. Simultaneously, the injection of SB328437 reduces the protein levels of some pronociceptive cytokines, such as IL-6, CCL7, and CCL11, in parallel with a reduction in the activation and influx of GFAP-, CD4- and MPO-positive cells in the spinal cord and/or DRG. Moreover, we have shown for the first time that an inhibitor of myeloperoxidase-4-aminobenzoic hydrazide may relieve pain and simultaneously enhance morphine and buprenorphine efficacy. The obtained results indicate the important role of CCR3 and its modulation in neuropathic pain treatment and suggest that it represents an interesting target for future investigations.

Topics: Analgesics; Analgesics, Opioid; Animals; Biomarkers; Buprenorphine; Disease Management; Disease Models, Animal; Disease Susceptibility; Drug Administration Schedule; Drug Synergism; Ganglia, Spinal; Gene Expression Regulation; Male; Mice; Morphine; Neuralgia; Rats; Receptors, CCR3; Spinal Cord; Time Factors; Treatment Outcome

A growing body of evidence has indicated that the release of nociceptive factors, such as interleukins and chemokines, by activated immune and glial cells has crucial significance for neuropathic pain generation and maintenance. Moreover, changes in the production of nociceptive immune factors are associated with low opioid efficacy in the treatment of neuropathy. Recently, it has been suggested that CC chemokine receptor type 1 (CCR1) signaling is important for nociception. Our study provides evidence that the development of hypersensitivity in rats following chronic constriction injury (CCI) of the sciatic nerve is associated with significant up-regulation of endogenous CCR1 ligands, namely, CCL2, CCL3, CCL4, CCL6, CCL7 and CCL9 in the spinal cord and CCL2, CCL6, CCL7 and CCL9 in dorsal root ganglia (DRG). We showed that single and repeated intrathecal administration of J113863 (an antagonist of CCR1) attenuated mechanical and thermal hypersensitivity. Moreover, repeated administration of a CCR1 antagonist enhanced the analgesic properties of morphine and buprenorphine after CCI. Simultaneously, repeated administration of J113863 reduced the protein levels of IBA-1 in the spinal cord and MPO and CD4 in the DRG and, as a consequence, the level of pronociceptive factors, such as interleukin-1β (IL-1β), IL-6 and IL-18. The data obtained provide evidence that CCR1 blockade reduces hypersensitivity and increases opioid-induced analgesia through the modulation of neuroimmune interactions.

Topics: Analgesics; Animals; Buprenorphine; Calcium-Binding Proteins; Chemokine CCL2; Disease Models, Animal; Drug Synergism; Ganglia, Spinal; Gene Expression Regulation; Hyperalgesia; Interleukin-18; Interleukin-1beta; Interleukin-6; Male; Microfilament Proteins; Morphine; Neuralgia; Nociception; Peroxidase; Protein Isoforms; Rats; Rats, Wistar; Receptors, CCR1; Sciatic Nerve; Signal Transduction; Xanthenes

Topics: Animals; Behavior, Animal; Biomarkers; Buprenorphine; Disease Models, Animal; Drug Synergism; Injections, Spinal; Male; Mice; Models, Animal; Morphine; Neuralgia; Pain Management; Quinazolines; Receptors, CCR4; Time Factors; Treatment Outcome

Topics: Analgesics; Analgesics, Opioid; Animals; Buprenorphine; CCR5 Receptor Antagonists; Cytokines; Dose-Response Relationship, Drug; Drug Synergism; Ganglia, Spinal; Gene Expression Regulation; Hyperalgesia; Imidazoles; Injections, Spinal; Male; Morphine; Nerve Tissue Proteins; Neuralgia; Rats; Rats, Wistar; Receptors, CCR2; Receptors, CCR5; Receptors, Opioid; RNA, Messenger; Sciatic Neuropathy; Spinal Cord; Sulfoxides

A patient with neurofibromatosis type 1 presented to the pain clinic with neuropathic pain. Thoracolumbar magnetic resonance imagining revealed meningocele T12-L2 with cauda equina distortion. After becoming pregnant, the patient interrupted opioid treatment, refusing pharmacological treatment until the pain became unbearable. Transcutaneous electrical nerve stimulation (TENS) was proposed. The patient used this treatment from the first trimester until month 6 postpartum, achieving good analgesia without any adverse effects for the mother or child. TENS may be a viable treatment for neuropathic pain (NP) during pregnancy. However, more data are needed due to the difficulty of conducting clinical trials in this population.

Topics: Adult; Analgesics, Opioid; Buprenorphine; Female; Humans; Neuralgia; Neurofibromatosis 1; Pregnancy; Transcutaneous Electric Nerve Stimulation

The urgent need for more effective analgesic treatment options has prompted a re-evaluation of the behavioral tests used to assess pain in pre-clinical research, with an emphasis on inclusion of more voluntary, un-evoked behavioral assessments of pain. In order to validate voluntary gait analysis and a voluntary mechanical conflict-avoidance assay, we tested mouse models of neuropathy (spared nerve injury) and inflammation (complete Freund's adjuvant) alongside reflexive measures of mechanical and thermal hypersensitivity. To establish whether the observed changes in behavioral responses were pain-related, known analgesics (buprenorphine, gabapentin, carprofen) were also administered. Spared nerve injury persistently altered several gait indices, whereas complete Freund's adjuvant caused only transient changes. Furthermore, known analgesics could not reverse these gait changes, despite demonstrating their previously established efficacy in reflexive measures of mechanical and thermal hypersensitivity. In contrast, the mechanical conflict-avoidance assay demonstrated aversion in mice with neuropathy and inflammation-induced hypersensitivity, which could both be reversed by analgesics. We conclude that voluntary gait changes in rodent neuropathic and inflammatory pain models are not necessarily indicative of pain-related adaptations. On the other hand, mechanical conflict-avoidance represents a valid operant assay for quantifying pain-related behaviors in mice that can be reversed by known analgesics.

Topics: Analgesics; Animals; Buprenorphine; Carbazoles; Disease Models, Animal; Female; Freund's Adjuvant; Gabapentin; Gait; Inflammation; Male; Mice; Mice, Inbred C57BL; Neuralgia; Pain Measurement

The mechanism of neuropathic pain is complex and unclear. Based on our results, we postulate that an intensification of the kynurenine pathway occurs as a consequence of nerve injury. The G protein-coupled receptor 35 (GPR35) is important for kynurenine pathway activation. Cyclic GMP-specific phosphodiesterase inhibitors have also been shown to have beneficial effects on neuropathic pain. Therefore, the aims of our research were to elucidate how a substance that acts as both an agonist of GPR35 and an inhibitor of phosphodiesterase influences neuropathic pain in a rat model. Here, we demonstrated that preemptive and repeated intrathecal (i.t.) administration (16 h and 1 h before injury and then after nerve ligation daily for 7 days) of zaprinast (1 μg/5 μl) significantly attenuated mechanical (von Frey test) and thermal (cold plate test) hypersensitivity measured on day 7 after chronic constriction injury, and the effect of even a single injection lasted up to 24 h. Our data indicate that zaprinast diminished the number of IBA1-positive cells and consequently attenuated the levels of IL-1beta, IL-6, IL-18, and NOS2 in the lumbar spinal cord and/or dorsal root ganglia. Our results also demonstrated that zaprinast potentiated the analgesic properties of morphine and buprenorphine. In summary, in a neuropathic pain model, zaprinast significantly reduced pain symptoms and enhanced the effectiveness of opioids. Our data provide new evidence that modulation of both GPR35 and phosphodiesterase could be an important strategy for innovative pharmacological treatments designed to decrease hypersensitivity evoked by nerve injury.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Calcium-Binding Proteins; Dose-Response Relationship, Drug; Drug Synergism; Ganglia, Spinal; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Microfilament Proteins; Morphine; Neuralgia; Neuroglia; Nociception; Purinones; Rats; Receptors, G-Protein-Coupled; Spinal Cord

A bifunctional peptide containing an opioid and nociceptin receptor-binding pharmacophore, H-Dmt-D-Arg-Aba-β-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2 (KGNOP1), was tested for its analgesic properties when administered intrathecally in naïve and chronic constriction injury (CCI)-exposed rats with neuropathy-like symptoms. KGNOP1 significantly increased the acute pain threshold, as measured by the tail-flick test, and also increased the threshold of a painful reaction to mechanical and thermal stimuli in CCI-exposed rats. Both of the effects could be blocked by pre-administration of [Nphe1]-Nociceptin (1-13)-NH

Topics: Acute Pain; Analgesics, Opioid; Animals; Behavior, Animal; Buprenorphine; Disease Models, Animal; Hot Temperature; Hyperalgesia; Morphine; Neuralgia; Nociceptin; Oligopeptides; Opioid Peptides; Pain Measurement; Physical Stimulation; Rats, Wistar

Chemokine signaling has been implicated in the pathogenesis of diabetic neuropathy; however, the involvement of the chemokine CC motif ligand 1 (CCL1)-chemokine CC motif receptor 8 (CCR8) interaction remains unknown. The goal of this study was to examine the role of CCL1-CCR8 signaling interplay in the development of hypersensitivity and in opioid effectiveness in diabetic neuropathy.. Primary glial cell cultures and a streptozotocin (STZ; 200mg/kg, intraperitoneal)-induced mouse model of diabetic neuropathy were used. Analysis of mRNA/protein expression of glial markers and CCL1/CCR8 was performed by qRT-PCR, Western blotting and/or protein arrays. The co-localization of CCL1/CCR8 with neural/glial cells was visualized by immunofluorescence. The pharmacological tools were injected intrathecally, and pain behavior was evaluated by von Frey/cold plate tests.. Single STZ injection increased blood glucose levels and induced the development of hypersensitivity as measured on days 7-21. On day 7 after STZ, the protein levels of CCL1 and IBA1 but not of CCR8 or GFAP were elevated. Immunofluorescent staining revealed that CCR8 was predominantly localized in neurons, which are also the main source of spinal CCL1. Lipopolysaccharide stimulation of primary microglial cultures resulted in decreases in the levels of CCL1 and CCR8. Single intrathecal injection of CCL1 (10-500ng) induced the development of hypersensitivity, whereas on day 7 after STZ, a CCL1-neutralizing antibody dose-dependently (2-8μg) delayed pain behavior. Repeated administration of the CCL1-neutralizing antibody (4μg) also enhanced the effectiveness of morphine and buprenorphine (1μg).. These results reveal that CCL1/CCR8 neuronal signaling plays an important role in the development of diabetic neuropathy and the effectiveness of opioids.

Topics: Animals; Antibodies, Blocking; Buprenorphine; Cells, Cultured; Chemokine CCL1; Diabetes Mellitus, Experimental; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Humans; Lipopolysaccharides; Male; Mice; Molecular Targeted Therapy; Morphine; Neuralgia; Neuroglia; Receptors, CCR8; Signal Transduction; Spine

Targeting chemokine signaling pathways is crucial in neuropathy development. In this study, we investigated the influence of chronic administration of maraviroc (CCR5 antagonist) on nociception and opioid effectiveness during neuropathy, which develops as a result of chronic constriction injury (CCI) of the sciatic nerve. To investigate the mechanism of action of maraviroc, we measured the expression of glial cell markers, CCR5 and certain CCR5 ligands (CCL3, CCL4, CCL5, CCL7, CCL11), in the spinal cord and dorsal root ganglia (DRG) of vehicle- and maraviroc-treated, CCI-exposed rats. Our results demonstrate that chronic intrathecal administration of maraviroc diminished neuropathic pain symptoms on day 7 post-CCI. Western blot analysis showed that maraviroc diminished protein level of Iba-1 and GFAP and reversed the up-regulated CCR5 expression observed in spinal cord and DRG after CCI. Additionally, using qRT-PCR, we demonstrated that CCR5 and some of its pronociceptive ligands (CCL3, CCL4, CCL5) increased in the spinal cord after nerve injury, and maraviroc effectively diminished those changes. However, CCL11 spinal expression was undetectable, even after injury. In vitro primary culture studies showed that CCL3, CCL4, CCL5 and CCL7 (but not CCL11) were of microglial and astroglial origin and were up-regulated after LPS stimulation. Our results indicate that maraviroc not only attenuated the development of neuropathic pain symptoms due to significant modulation of neuroimmune interactions but also intensified the analgesic properties of morphine and buprenorphine. In sum, our results suggest the pharmacological modulation of CCR5 by maraviroc as a novel therapeutic approach for co-treatment of patients receiving opioid therapy for neuropathy.

Topics: Analgesics, Opioid; Animals; Astrocytes; Buprenorphine; CCR5 Receptor Antagonists; Cells, Cultured; Chronic Disease; Cyclohexanes; Cytokines; Disease Models, Animal; Drug Synergism; Ganglia, Spinal; Hyperalgesia; Lipopolysaccharides; Male; Maraviroc; Microglia; Morphine; Neuralgia; Rats, Wistar; Sciatic Nerve; Spinal Cord; Triazoles

Currently, the low efficacy of antinociceptive drugs for the treatment of neuropathic pain is a major therapeutic problem. Here, we show the potential role of interleukin (IL)-18 signaling in this phenomenon. IL-18 is an important molecule that performs various crucial functions, including the alteration of nociceptive transmission in response to neuropathic pain. We have studied the changes in the mRNA and protein levels (qRT-PCR and Western blot analysis, respectively) of IL-18, IL-18-binding protein (IL-18BP) and the IL-18 receptor (IL-18R) over time in rats following chronic constriction injury (CCI) of the sciatic nerve. Our study demonstrated that the spinal levels of IL-18BP were slightly downregulated at days 7 and 14 in the rats subjected to CCI. In contrast, the IL-18 and IL-18R mRNA expression and protein levels were elevated in the ipsilateral spinal cord on days 2, 7 and 14. Moreover, in rats exposed to a single intrathecal administration of IL-18BP (50 and 100 ng) 7 or 14 days following CCI, symptoms of neuropathic pain were attenuated, and the analgesia pursuant to morphine and buprenorphine (0.5 and 2.5 μg) was enhanced. In summary, the restoration of the analgesic activity of morphine and buprenorphine via the blockade of IL-18 signaling suggests that increased IL-18 pathway may account for the decreased analgesic efficacy of opioids for neuropathic pain.

Topics: Analgesics, Opioid; Animals; Astrocytes; Buprenorphine; Cells, Cultured; Drug Synergism; Intercellular Signaling Peptides and Proteins; Interleukin-18; Male; Morphine; Neuralgia; Neurons; Rats; Rats, Wistar; Receptors, Interleukin-18; Spinal Cord

Accumulating evidence indicates that microglial TLR2 and TLR4 play a significant role in nociception. Experiments were conducted to evaluate the contribution of TLR2 and TLR4 and their adaptor molecules to neuropathy and their ability to amplify opioid effectiveness. Behavioral tests (von Frey's and cold plate) and biochemical (Western blot and qRT-PCR) analysis of spinal cord and DRG tissue were conducted after chronic constriction injury (CCI) to the sciatic nerve. Repeated intrathecal administration of LPS-RS (TLR2 and TLR4 antagonist) and LPS-RS Ultrapure (TLR4 antagonist) attenuated allodynia and hyperalgesia. Biochemical analysis revealed time-dependent upregulation of mRNA and/or protein levels of TLR2 and TLR4 and MyD88 and TRIF adaptor molecules, which was paralleled by an increase in IBA-1/CD40-positive cells under neuropathy. LPS-RS and LPS-RS Ultrapure similarly influenced opioid analgesia by enhancing the effectiveness of buprenorphine but not morphine. Summing up, in light of their upregulation over the course of pain, both TLR2 and TLR4 may indeed play a significant role in neuropathy, which could be linked to the observed activation of IBA-1/CD40-positive cells. Blockade of TLR2 and TLR4 produced analgesia and enhanced buprenorphine's effectiveness, which suggests that they may be a putative target for future pharmacological pain relief tools, especially for opioid rotation, when the effect of morphine is tolerated.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Disease Models, Animal; Ganglia, Spinal; Hyperalgesia; Lipopolysaccharides; Male; Neuralgia; Rats; Rats, Wistar; Sciatic Nerve; Spinal Cord; Toll-Like Receptor 2; Toll-Like Receptor 4

An interesting research and therapeutic problem is the reduced beneficial efficacy of opioids in the treatment of neuropathic pain. The present study sought to investigate the potential role of IL-1 family members in this phenomenon. We studied the time course of changes in IL-1alpha, IL-1beta, IL-1 receptor type I and IL-1 receptor antagonist mRNA and protein levels experienced by rats after chronic constriction injury (CCI) of the sciatic nerve using qRT-PCR and Western blot analysis. In CCI-exposed rats, spinal levels of IL-1alpha mRNA were slightly downregulated on the 7th day, and protein levels were not changed on the 7th and 14th days. Levels of IL-1 receptor antagonist and IL-1 receptor type I were slightly upregulated in the ipsilateral part of the spinal cord on the 7th and 14th days; however, protein levels were not changed at those time points. Interestingly, we observed that IL-1beta mRNA and protein levels were strongly elevated in the ipsilateral part of the dorsal spinal cord on the 7th and 14th days following CCI. Moreover, in rats exposed to a single intrathecal administration of an IL-1 receptor antagonist (100 ng i.t.) on the 7th and 14th day following CCI, symptoms of neuropathic pain were attenuated, and the analgesic effects of morphine (2.5 µg i.t.) and buprenorphine (2.5 µg i.t.) were enhanced. In summary, restoration of the analgesic activity of morphine and buprenorphine by blockade of IL-1 signaling suggests that increased IL-1beta responses may account for the decreased analgesic efficacy of opioids observed in the treatment of neuropathy.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Hyperalgesia; Interleukin 1 Receptor Antagonist Protein; Interleukin-1alpha; Interleukin-1beta; Male; Morphine; Neuralgia; Rats, Wistar; RNA, Messenger; Sciatic Nerve; Spinal Cord; Treatment Outcome

This study was designed to investigate the efficacy of a partial μ-opioid agonist, buprenorphine, against the formalin-induced hyperalgesia in the upper lip in chronically inferior alveolar nerve (IAN)-transected rats. Subcutaneous injection of diluted formalin into the upper lip in the IAN-transected rats showed an increased number of pain-related behavior (PRB; face-rubbing behavior) in every phase up to 45 min (p < 0.01) compared with that in the nontransected sham control rats. The numbers of c-Fos-immunoreactive (IR) cells in the superficial layers of the trigeminal nucleus caudalis (VcI/II) at the rostral (0-0.7 mm caudal to the obex) and middle levels (1.4-2.2 mm caudal to the obex) 2 h after the formalin injection in the IAN-transected rats were significantly increased compared with those in the control rats. The PRB in phases 1 and 2 (0-15 and 15-30 min after formalin injection) in rats with preadministration of morphine (3 mg/kg i.p.) or buprenorphine (100 µg/kg i.p.) was significantly (p < 0.05) smaller than those in the control rats. There was no significant difference in the efficacy between morphine and buprenorphine at these doses. The antinociceptive efficacy in phase 2 of buprenorphine (100 µg/kg) was higher (p < 0.05) than that of morphine (3 mg/kg) in the IAN-transected rats. The number of c-Fos-IR cells in the VcI/II at every level (0-3.6 mm caudal to the obex) after formalin injection was significantly decreased (p < 0.01) with preadministration of morphine (3 mg/kg) or buprenorphine (100 µg/kg) in the control rats. In the IAN-transected rats, the number of c-Fos-IR cells in the caudal VcI/II (2.2-3.6 mm caudal to the obex) after formalin injection was significantly decreased (p < 0.01) with preadministration of buprenorphine (100 µg/kg) but not so much (2.2-2.9 mm caudal to the obex, p < 0.05; 2.9-3.6 mm caudal to the obex, p > 0.05) with preadministration of morphine (3 mg/kg). These results indicate that IAN transection enhanced formalin-induced nocifensive responses in the upper lip, the dermatome of the intact nerve neighboring the IAN. Systemic preadministration of buprenorphine had more antinociceptive effects on the formalin-induced nocifensive behavior in the upper lip compared with morphine in the IAN-transected rats.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Buprenorphine; Formaldehyde; Lip; Male; Mandibular Nerve; Morphine; Narcotic Antagonists; Neuralgia; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Trigeminal Nerve Injuries

Buprenorphine is a frequently used opioid in the treatment of neuropathic pain component that is often present in patients with cancer. A case of a 41-year-old patient was depicted whose pain syndrome was associated with the chondrosarcoma growth originating from the sacral bone and numerous surgical interventions and radiotherapy. Improvement in analgesia and good toleration of therapy were observed after switching from transdermal fentanyl to transdermal buprenorphine while maintaining treatment with antidepressants and anticonvulsants. This case report indicates a possibility of a safe switch of transdermal opioids at home, which may provide benefits in terms of analgesia and adverse effects and in consequence have positive impact on the patients' quality of life. This is also accompanied by constant psychological, social, and spiritual support provided to the patient and family.

Topics: Administration, Cutaneous; Adult; Analgesics, Opioid; Buprenorphine; Drug Substitution; Female; Fentanyl; Humans; Neuralgia; Palliative Care; Quality of Life

Multifactor neuropathic pain is one of the most frequent symptoms in AIDS patients and analgesic treatment is primarily based on the use of drug combination of opioids, tricyclic antidepressants and antiepileptics. However, the chronic use of opioids in AIDS patients presents a risk due to the immunosuppressive action of these drugs. Until now, buprenorphine has been regarded as one of the safest opioid analgesics for the treatment of patients with compromised immune systems. To assess the suitability of transdermal fentanyl for the treatment of neuropathic pain in AIDS patients, the present study compares the efficacy, tolerability and the immunosuppressive effects of transdermal buprenorphine vs. fentanyl.. Forty advanced AIDS patients (28 male and 12 female) with chronic peripheral neuropathic pain were enrolled onto this clinical trial. Neuropathic pain was assessed for its constituent types of pain (burning, stabbing and shooting), its overall intensity and allodynia; scores were awarded using the Neuropathic Pain Scale, expressed as 10 item VAS scores.. Both treatment groups showed statistically significant reductions in each of the individual types of neuropathic pain and allodynia (P<0.05; 95% CI: -14.7, -3.1) and significant improvements in Karnofsky Performance Status (P<0.05; mean value, 69; range: 40-90). Both buprenorphine and fentanyl were well tolerated. Neither buprenorphine nor fentanyl affected CD4+ or CD8+levels and both treatments, but particularly buprenorphine group, resulted in more stable CD4+ concentrations.. The high efficacy, tolerability and patient compliance of both buprenorphine and fentanyl make both these two opioids valid therapeutic options for the treatment of neuropathic pain in patients with AIDS.

Topics: Acquired Immunodeficiency Syndrome; Adult; Analgesics, Opioid; Buprenorphine; CD4-CD8 Ratio; Female; Fentanyl; Humans; Karnofsky Performance Status; Male; Middle Aged; Neuralgia; Pain Measurement; Patient Satisfaction; Transdermal Patch; Treatment Outcome

We evaluated the effect of buprenorphine, a mixed agonist for μ-opioid receptors and nociceptin/orphanin FQ peptide (NOP) receptors, in neuropathic rats, using the paw pressure test. Buprenorphine, administered i.p. at 50, but not 20, μg/kg, exhibited naloxone-reversible analgesic activity in naïve rats. In contrast, buprenorphine at 0.5 - 20 μg/kg produced a naloxonesensitive antihyperalgesic effect in the L5 spinal nerve-injured neuropathic rats. Intrathecal injection of [N-Phe(1)]nociceptin(1-13)NH2, a NOP-receptor antagonist, reversed the effect of buprenorphine in neuropathic rats, but not in naïve rats. Together, buprenorphine suppresses neuropathic hyperalgesia by activating NOP and opioid receptors, suggesting its therapeutic usefulness in treatment of neuropathic pain.

Topics: Analgesics; Animals; Buprenorphine; Male; Neuralgia; Nociceptin Receptor; Rats; Rats, Wistar; Receptors, Opioid; Receptors, Opioid, mu; Spinal Nerves

Topics: Acquired Immunodeficiency Syndrome; Analgesics, Opioid; Buprenorphine; Female; Fentanyl; Humans; Male; Neuralgia

Nociceptin/orphanin FQ peptide receptor (NOP) agonists produce antinociceptive effects in animal models after spinal administration and potentiate μ-opioid receptor (MOP)-mediated antinociception. This study determined the antinociceptive effects of spinally administered bifunctional NOP/MOP ligands and the antinociceptive functions of spinal NOP and MOP receptors in mice. Antinociceptive effects of bifunctional NOP/MOP ligands BU08028 [(2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol] and SR16435 [1-(1-(2,3,3α,4,5,6-hexahydro-1H-phenalen-1-yl)piperidin-4-yl)-indolin-2-one] were pharmacologically compared with the putative bifunctional ligand buprenorphine, selective NOP agonist SCH221510 [3-endo-8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol] and selective MOP agonist morphine in neuropathic and inflammatory pain models. Additionally, the degree of tolerance development to the antiallodynic effects of SR16435 and buprenorphine were determined after repeated intrathecal administration. Our data indicated that BU08028 and SR16435 were more potent than morphine and SCH221510 in attenuating nerve injury-induced tactile allodynia and inflammation-induced thermal hyperalgesia. Coadministration of receptor-selective antagonists further revealed that both NOP and MOP in the spinal cord mediated the antiallodynic effects of BU08028 and SR16435, but intrathecal buprenorphine-induced antiallodynic effects were primarily mediated by MOP. Repeated intrathecal administration of SR16435 resulted in reduced and slower development of tolerance to its antiallodynic effects compared with buprenorphine. In conclusion, both NOP and MOP receptors in the spinal cord independently drive antinociception in mice. Spinally administered bifunctional NOP/MOP ligands not only can effectively attenuate neuropathic and inflammatory pain, but also have higher antinociceptive potency with reduced tolerance development to analgesia. Such ligands therefore display a promising profile as spinal analgesics.

Topics: Analgesics, Opioid; Anesthesia, Spinal; Animals; Azabicyclo Compounds; Buprenorphine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Hyperalgesia; Indoles; Injections, Spinal; Ligands; Male; Mice; Mice, Inbred ICR; Molecular Targeted Therapy; Narcotic Antagonists; Nerve Tissue Proteins; Neuralgia; Neurons; Nociceptin Receptor; Phenalenes; Receptors, Opioid; Receptors, Opioid, mu; Spinal Cord

Phantom limb pain is a common consequence of limb amputation and is prevalent among the service members sustaining traumatic battlefield limb injuries during the conflicts in Iraq and Afghanistan. Current treatment to relieve phantom limb pain consists of physical, behavioral, and medical modalities including opioids and adjunct medications. Treatment failure resulting in persistent pain and disability may result. This case series describes four previously healthy service members who developed phantom limb pain following traumatic amputation successfully treated with buprenorphine/naloxone after failing traditional treatment. This is the first reported case series of patients expressing improved pain control with decreased frequency of phantom limb pain with the use of buprenorphine/naloxone instead of traditional opioid agonists.

Topics: Adult; Amputation, Traumatic; Analgesics, Opioid; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Humans; Male; Middle Aged; Military Personnel; Naloxone; Neuralgia; Phantom Limb; Young Adult

Topics: Administration, Cutaneous; Administration, Oral; Analgesics, Opioid; Buprenorphine; Drug Therapy, Combination; Humans; Lung Neoplasms; Methadone; Middle Aged; Morphine; Musculoskeletal Pain; Neuralgia; Palliative Care

Topics: Aged; Buprenorphine; Humans; Male; Morphinans; Neuralgia; Urination Disorders