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British Journal of Clinical Pharmacology Apr 2023We describe the distribution of prescribers responsible for opioid initiation and maintenance (general practice, hospital prescribers and other prescribers) in Denmark.
AIMS
We describe the distribution of prescribers responsible for opioid initiation and maintenance (general practice, hospital prescribers and other prescribers) in Denmark.
METHODS
We leveraged data on opioid fills from a 20% sample of all Danes alive during 2000-2021.
RESULTS
Overall, general practitioners were responsible for most treatment initiation (74% during 2000-2021) and maintenance treatment (92%). However, while hospital prescribers initiated ≈20% of treatments during 2001-2012, this increased to 35% in 2021. Similarly, hospital prescriber's share of maintenance treatment increased from 5.9% during 2000-2012 to 13% in 2021. This change was particularly pronounced for morphine initiation (48% hospital prescribers in 2021 up from 38% during 2000-2010) and oxycodone initiation (78% up from 41%). Regarding choice of opioids, codeine use dropped markedly, in particular among hospital prescribers. Tramadol was consistently the most common first choice opioid in general practice (33% in 2021), whereas its use among hospital prescribers decreased (54% during 2000-2015 to 15% in 2021). Conversely, the proportion of treatment initiation by hospital prescribers composed of morphine and oxycodone increased to 38% and 42% in 2021, respectively.
CONCLUSIONS
General practice prescribes most opioids; however, hospital prescribers are increasingly responsible for opioid prescribing, in particular initiation of morphine and oxycodone.
Topics: Humans; Analgesics, Opioid; Oxycodone; Practice Patterns, Physicians'; Morphine; Drug Utilization; Drug Prescriptions
PubMed: 36366867
DOI: 10.1111/bcp.15595 -
The Medical Clinics of North America Jul 2018Despite the availability of effective medications and psychosocial interventions for the management of a substance use disorder, some individuals repeatedly fail the... (Review)
Review
Despite the availability of effective medications and psychosocial interventions for the management of a substance use disorder, some individuals repeatedly fail the most aggressive treatment regimens. For such individuals, alternative treatment options exist seeking to mitigate the negative consequences of the use of harmful substances. Participation in a managed alcohol program, or the use of sustained-release oral morphine or injectable opioid agonist treatment or the creation of safe injecting facilities, are examples of such nonstandard approaches. This article reviews the available evidence of these treatment modalities.
Topics: Alcohol-Related Disorders; Analgesics, Opioid; Delayed-Action Preparations; Heroin; Humans; Morphine; Opioid-Related Disorders; Public Housing; Randomized Controlled Trials as Topic; Severity of Illness Index
PubMed: 29933823
DOI: 10.1016/j.mcna.2018.02.006 -
TheScientificWorldJournal 2015Pain is a hallmark of sickle cell disease (SCD) and its treatment remains challenging. Opioids are the major family of analgesics that are commonly used for treating... (Review)
Review
Pain is a hallmark of sickle cell disease (SCD) and its treatment remains challenging. Opioids are the major family of analgesics that are commonly used for treating severe pain. However, these are not always effective and are associated with the liabilities of their own. The pharmacology and multiorgan side effects of opioids are rapidly emerging areas of investigation, but there remains a scarcity of clinical studies. Due to opioid-induced endothelial-, mast cell-, renal mesangial-, and epithelial-cell-specific effects and proinflammatory as well as growth influencing signaling, it is likely that when used for analgesia, opioids may have organ specific pathological effects. Experimental and clinical studies, even though extremely few, suggest that opioids may exacerbate existent organ damage and also stimulate pathologies of their own. Because of the recurrent and/or chronic use of large doses of opioids in SCD, it is critical to evaluate the role and contribution of opioids in many complications of SCD. The aim of this review is to initiate inquiry to develop strategies that may prevent the inadvertent effect of opioids on organ function in SCD, should it occur, without compromising analgesia.
Topics: Analgesics, Opioid; Anemia, Sickle Cell; Humans; Morphine; Pain; Pain Management
PubMed: 25654130
DOI: 10.1155/2015/540154 -
Tissue & Cell Feb 2021Cancer pain, especially bone cancer pain, is a pain state often caused by inflammation or dysfunctional nerves. Moreover, in the management of cancer pain, opioid... (Review)
Review
Cancer pain, especially bone cancer pain, is a pain state often caused by inflammation or dysfunctional nerves. Moreover, in the management of cancer pain, opioid especially morphine is widely used, however, it also brings severe side effects such as morphine tolerance to the patient (Deandrea et al., 2008). A growing body of literatures demonstrated that neuroinflammation is mediated by microglia. As the macrophages like immune cells, microglia play an important role in the pathogenesis of cancer pain and morphine tolerance. Microglia acquire different activation states to regulate the function of these cells. As to M1 phenotype, microglia release pro-inflammatory cytokines and neurotoxic molecules that promote inflammation and cytotoxic reactions. Conversely, when microglia represent M2 phenotypes secreting anti-inflammatory cytokines and nutrient factors that promote the function of repair, regeneration and restore homeostasis. A better understanding of microglia activation in cancer pain and morphine tolerance is crucial for the development of hypothesized neuroprotective drugs. Targeting microglia different polarization states by the inhibition of their deleterious pro-inflammatory neurotoxicity and/or enhancing their beneficial anti-inflammatory protective function seems to be an effective treatment for cancer pain and morphine tolerance.
Topics: Animals; Cancer Pain; Drug Tolerance; Humans; Inflammation; Microglia; Models, Biological; Morphine
PubMed: 33220596
DOI: 10.1016/j.tice.2020.101438 -
CPT: Pharmacometrics & Systems... Jan 2022Intravenous (i.v.) morphine is a safe, robust, and recommended treatment for severe pain using the titration principle. Despite its high efficacy, it is impacted by...
Intravenous (i.v.) morphine is a safe, robust, and recommended treatment for severe pain using the titration principle. Despite its high efficacy, it is impacted by organizational constraints related to venous access. Nebulized (NEB) morphine may represent an alternative for titration but pharmacokinetic (PK) properties of short nebulization using routine devices need evaluation. Twenty-seven healthy volunteers were included to receive NEB or i.v. morphine administration using increasing amounts according to Dixon's reference method. Plasma morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) were quantified. PK modeling and simulations were performed using Monolix. Dixon's method exhibited a significantly higher morphine dose regimen in the NEB group versus the i.v. group (6.2 [5.3-7.1] vs. 3.0 [2.0-4.0] mg, p < 0.001). Morphine, M3G, and M6G dose-normalized exposure were significantly lower in the NEB group versus the i.v. group: morphine (19 [13-23] vs. 1044 [702-1266] µg min/L, p < 0.001), M3G (245 [162-287] vs. 3752 [2487-5165] µg min/L, p < 0.001) and M6G (28 [21-43] vs. 466 [370-723] µg min/L, p < 0.001). The model that best fitted the data consisted in a transit compartment for morphine absorption, three compartments for morphine distribution followed by multiple transit compartments (8.2 and 57.5-min transit time for M3G and M6G, respectively) and a first order elimination for M3G and M6G. Morphine bioavailability in the NEB group was 3.5% using the i.v. group as reference. Administration route and sex significantly influenced morphine and metabolite PKs. This work aimed to evaluate the PKs of NEB morphine compared with the i.v. route. Despite a bioavailability to improve, NEB morphine administration using a routine device is suitable to plan morphine titration.
Topics: Administration, Inhalation; Adult; Analgesics, Opioid; Computer Simulation; Dose-Response Relationship, Drug; Female; Healthy Volunteers; Humans; Injections, Intravenous; Male; Middle Aged; Models, Biological; Morphine; Morphine Derivatives; Nebulizers and Vaporizers; Sex Factors
PubMed: 34842366
DOI: 10.1002/psp4.12735 -
Journal of Pharmacological Sciences Apr 2023ASP8062 is an orally available GABA receptor positive allosteric modulator (PAM). This study assessed the potential of ASP8062 for treating opioid use disorder (OUD)....
ASP8062 is an orally available GABA receptor positive allosteric modulator (PAM). This study assessed the potential of ASP8062 for treating opioid use disorder (OUD). Three rhesus monkeys were pretreated with ASP8062 (0.3, 1 or 3 mg/kg) by oral administration 1 h prior to a 2-h morphine self-administration session (0.03 mg/kg, iv, per injection) under a fixed-ratio 5 schedule. We further examined the potential worsening of morphine-induced respiratory suppression by ASP8062 after coadministration of morphine (10 mg/kg, sc) and ASP8062 (10 mg/kg, po) in cynomolgus monkeys using a custom-made whole-body plethysmograph. Plasma concentrations of ASP8062 (3 or 10 mg/kg, po) were assessed in cynomolgus monkeys using liquid chromatography-tandem mass spectroscopy (LC-MS/MS). ASP8062 at 3 mg/kg, po decreased the morphine self-administrations with significant differences from the vehicle-treated group (IC = 0.97 ± 0.36 mg/kg). Exposure levels at 3 mg/kg observed in monkeys were comparable to the clinical exposure levels which positive pharmacodynamic effects were previously shown. Further, ASP8062 did not potentiate morphine-induced respiratory suppression up to exposure levels higher than the clinically relevant dose. ASP8062 may reduce opioid use in OUD patients without affecting respiratory system, providing justification for further ASP8062 development as a potential treatment option for OUD.
Topics: Animals; Morphine; Macaca fascicularis; Chromatography, Liquid; Tandem Mass Spectrometry; Dose-Response Relationship, Drug
PubMed: 36925215
DOI: 10.1016/j.jphs.2023.02.003 -
European Review For Medical and... Mar 2021This study aimed to assess the efficacy and safety of intrathecal (IT) morphine for postoperative pain control in adults undergoing spinal surgeries. We searched the... (Meta-Analysis)
Meta-Analysis
This study aimed to assess the efficacy and safety of intrathecal (IT) morphine for postoperative pain control in adults undergoing spinal surgeries. We searched the electronic databases of PubMed, Embase, and CENTRAL up to 1st January 2021 for randomized controlled trials (RCTs) or controlled clinical trials (CCTs) comparing IT morphine with placebo or other analgesics. Twelve studies were included. Eleven were RCTs and one was a CCT. Our meta-analysis indicated a statistically significant reduction of pain scores with IT morphine at 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours; but no significant difference at 48 hours. Meta-analysis indicated a statistically significant reduction in analgesic consumption with IT morphine as compared to control. Pooled analysis indicated that IT morphine had no statistically significant effect on length of hospital stay. Our analysis indicated no statistically significant difference in the risk of nausea, vomiting, sedation, respiratory depression, headache, and urinary retention between IT morphine and control groups. The incidence of pruritis was significantly increased in the IT morphine group. The certainty of the evidence was judged to be "moderate" for pain scores at 12 hours, 24 hours, and analgesic consumption. To conclude, our review indicates that IT morphine results in significantly better pain control in the first 24 hours after spinal surgery. The risk of pruritis is significantly increased with the use of IT morphine but not for other opioid-related adverse events. Future RCTs should focus on finding the most optimal dose of IT morphine for spinal surgeries.
Topics: Analgesics; Humans; Injections, Spinal; Morphine; Pain Management; Pain, Postoperative; Spine
PubMed: 33829454
DOI: 10.26355/eurrev_202103_25431 -
PloS One 2015The purpose of this study was to compare the efficacy and safety of a single-dose intra-articular morphine plus bupivacaine versus morphine alone in patients undergoing... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
The purpose of this study was to compare the efficacy and safety of a single-dose intra-articular morphine plus bupivacaine versus morphine alone in patients undergoing arthroscopic knee surgery.
METHODS
Randomized controlled trials comparing a combination of morphine and bupivacaine with morphine alone injected intra-articularly in the management of pain after knee arthrocopic surgery were retrieved (up to August 10, 2014) from MEDLINE, the Cochrane Library and Embase databases. The weighted mean difference (WMD), relative risk (RR) and their corresponding 95% confidence intervals (CIs) were calculated using RevMan statistical software.
RESULTS
Thirteen randomized controlled trials were included. Statistically significant differences were observed with regard to the VAS values during the immediate period (0-2h) (WMD -1.16; 95% CI -2.01 to -0.31; p = 0.007) and the time to first request for rescue analgesia (WMD = 2.05; 95% CI 0.19 to 3.92; p = 0.03). However, there was no significant difference in the VAS pain score during the early period (2-6h) (WMD -0.36; 95% CI -1.13 to 0.41; p = 0.35), the late period (6-48h) (WMD 0.11; 95% CI -0.40 to 0.63; p = 0.67), and the number of patients requiring supplementary analgesia (RR = 0.78; 95% CI 0.57 to 1.05; p = 0.10). In addition, systematic review showed that intra-articular morphine plus bupivacaine would not increase the incidence of adverse effects compared with morphine alone.
CONCLUSION
The present study suggested that the administration of single-dose intra-articular morphine plus bupivacaine provided better pain relief during the immediate period (0-2h), and lengthened the time interval before the first request for analgesic rescue without increasing the short-term side effects when compared with morphine alone.
LEVEL OF EVIDENCE
Level I, meta-analysis of Level I studies.
Topics: Arthroscopy; Bupivacaine; Humans; Knee; Knee Joint; Morphine; Pain Management
PubMed: 26474401
DOI: 10.1371/journal.pone.0140512 -
Mu Opioid Receptor-Positive Neurons in the Dorsal Raphe Nucleus Are Impaired by Morphine Abstinence.Biological Psychiatry Dec 2023Chronic opioid exposure leads to hedonic deficits and enhanced vulnerability to addiction, which are observed and even strengthen after a period of abstinence, but the...
BACKGROUND
Chronic opioid exposure leads to hedonic deficits and enhanced vulnerability to addiction, which are observed and even strengthen after a period of abstinence, but the underlying circuit mechanisms are poorly understood. In this study, using both molecular and behavioral approaches, we tested the hypothesis that neurons expressing mu opioid receptors (MORs) in the dorsal raphe nucleus (DRN) are involved in addiction vulnerability associated with morphine abstinence.
METHODS
MOR-Cre mice were exposed to chronic morphine and then went through spontaneous withdrawal for 4 weeks, a well-established mouse model of morphine abstinence. We studied DRN-MOR neurons of abstinent mice using 1) viral translating ribosome affinity for transcriptome profiling, 2) fiber photometry to measure neuronal activity, and 3) an opto-intracranial self-stimulation paradigm applied to DRN-MOR neurons to assess responses related to addiction vulnerability including persistence to respond, motivation to obtain the stimulation, self-stimulation despite punishment, and cue-induced reinstatement.
RESULTS
DRN-MOR neurons of abstinent animals showed a downregulation of genes involved in ion conductance and MOR-mediated signaling, as well as altered responding to acute morphine. Opto-intracranial self-stimulation data showed that abstinent animals executed more impulsive-like and persistent responses during acquisition and scored higher on addiction-like criteria.
CONCLUSIONS
Our data suggest that protracted abstinence to chronic morphine leads to reduced MOR function in DRN-MOR neurons and abnormal self-stimulation of these neurons. We propose that DRN-MOR neurons have partially lost their reward-facilitating properties, which in turn may lead to increased propensity to perform addiction-related behaviors.
Topics: Mice; Animals; Morphine; Dorsal Raphe Nucleus; Receptors, Opioid, mu; Analgesics, Opioid; Neurons
PubMed: 37393045
DOI: 10.1016/j.biopsych.2023.06.024 -
British Journal of Pharmacology Dec 2022Misuse of opioids has greatly affected our society. One potential solution is to develop analgesics that act at targets other than opioid receptors. These can be used...
BACKGROUND AND PURPOSE
Misuse of opioids has greatly affected our society. One potential solution is to develop analgesics that act at targets other than opioid receptors. These can be used either as stand-alone therapeutics or to improve the safety profile of opioid drugs. Previous research showed that activation of G proteins by G-protein coupled receptors has pro-nociceptive properties, suggesting that blockade of G signalling could be beneficial for pain control. The aim of this study was to test this hypothesis pharmacologically by using potent and selective G inhibitor YM-254890.
EXPERIMENTAL APPROACH
We used a series of behavioural assays to evaluate the acute responses of mice to painful thermal stimulation while administering YM-254890 alone and in combination with morphine. We then used electrophysiological recordings to evaluate the effects of YM-254890 on the excitability of dorsal root ganglion (DRG) nociceptor neurons.
KEY RESULTS
We found that systemic administration of YM-254890 produced anti-nociceptive effects and also augmented morphine analgesia in both hotplate and tail flick paradigms. However, it also caused substantial inhibition of locomotion, which may limit its therapeutic utility. To circumvent these issues, we explored the local administration of YM-254890. Intrathecal injections of YM-254890 produced lasting analgesia in a tail flick test and greatly augmented the anti-nociceptive effects of morphine without any significant effects on locomotor behaviour. Electrophysiological studies showed that YM-254890 reduced the excitability of DRG nociceptors and augmented their opioid-induced inhibition.
CONCLUSION AND IMPLICATIONS
These findings indicate that pharmacological inhibition of G could be explored as an analgesic strategy.
Topics: Animals; Mice; Analgesics; Analgesics, Opioid; Morphine; Pain; Receptors, Opioid; GTP-Binding Protein alpha Subunits, Gq-G11
PubMed: 35900909
DOI: 10.1111/bph.15935