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Pharmacological Reviews Nov 2023Oxycodone, a semisynthetic derivative of naturally occurring thebaine, an opioid alkaloid, has been available for more than 100 years. Although thebaine cannot be used... (Review)
Review
Oxycodone, a semisynthetic derivative of naturally occurring thebaine, an opioid alkaloid, has been available for more than 100 years. Although thebaine cannot be used therapeutically due to the occurrence of convulsions at higher doses, it has been converted to a number of other widely used compounds that include naloxone, naltrexone, buprenorphine, and oxycodone. Despite the early identification of oxycodone, it was not until the 1990s that clinical studies began to explore its analgesic efficacy. These studies were followed by the pursuit of several preclinical studies to examine the analgesic effects and abuse liability of oxycodone in laboratory animals and the subjective effects in human volunteers. For a number of years oxycodone was at the forefront of the opioid crisis, playing a significant role in contributing to opioid misuse and abuse, with suggestions that it led to transitioning to other opioids. Several concerns were expressed as early as the 1940s that oxycodone had significant abuse potential similar to heroin and morphine. Both animal and human abuse liability studies have confirmed, and in some cases amplified, these early warnings. Despite sharing a similar structure with morphine and pharmacological actions also mediated by the -opioid receptor, there are several differences in the pharmacology and neurobiology of oxycodone. The data that have emerged from the many efforts to analyze the pharmacological and molecular mechanism of oxycodone have generated considerable insight into its many actions, reviewed here, which, in turn, have provided new information on opioid receptor pharmacology. SIGNIFICANCE STATEMENT: Oxycodone, a -opioid receptor agonist, was synthesized in 1916 and introduced into clinical use in Germany in 1917. It has been studied extensively as a therapeutic analgesic for acute and chronic neuropathic pain as an alternative to morphine. Oxycodone emerged as a drug with widespread abuse. This article brings together an integrated, detailed review of the pharmacology of oxycodone, preclinical and clinical studies of pain and abuse, and recent advances to identify potential opioid analgesics without abuse liability.
Topics: Animals; Humans; Oxycodone; Thebaine; Analgesics, Opioid; Opioid-Related Disorders; Morphine; Receptors, Opioid
PubMed: 37321860
DOI: 10.1124/pharmrev.121.000506 -
British Journal of Anaesthesia Nov 2023Open major abdominal surgery is one of the most risky surgical procedures for acute postoperative pain. Thoracic epidural analgesia (TEA) has been considered the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Open major abdominal surgery is one of the most risky surgical procedures for acute postoperative pain. Thoracic epidural analgesia (TEA) has been considered the standard analgesic approach. In different reports, lidocaine i.v. has been shown to have an analgesic efficacy comparable with TEA. We compared the analgesic efficacy of i.v. lidocaine with thoracic epidural analgesia using bupivacaine in patients undergoing major abdominal surgery.
METHODS
In this noninferiority clinical trial, 210 patients were randomised to thoracic epidural bupivacaine with morphine or i.v. lidocaine. Dynamic pain at 24 h after surgery was measured using a numerical pain rating scale (NPR), and morphine consumption was also measured. A difference in i.v. the lidocaine-epidural bupivacaine NPR of ≤1 for dynamic pain was considered a noninferiority margin.
RESULTS
The NPR for dynamic pain in the lidocaine group at 24 h was between 5.7 (1.8) and 5.2 (1.9) in the epidural group, with a difference of 0.53 (95% confidence interval 0.0-1.0). In the first 24 h, the average difference in morphine consumption was 1.8 mg between the i.v. lidocaine and epidural groups (95% confidence interval 1-3 mg). No differences were found in adverse events or complications associated with the procedures.
CONCLUSIONS
Intravenous lidocaine is noninferior to thoracic epidural analgesia for acute postoperative pain control in major abdomial surgery at 24 h postoperatively.
CLINICAL TRIALS REGISTRATION
NCT04017013.
Topics: Humans; Analgesia, Epidural; Analgesia, Patient-Controlled; Analgesics, Opioid; Anesthetics, Local; Bupivacaine; Lidocaine; Morphine; Pain, Postoperative
PubMed: 37758623
DOI: 10.1016/j.bja.2023.07.032 -
Inflammopharmacology Feb 2024There is documentation of the use of opium derived products in the ancient history of the Assyrians: the Egyptians; in the sixth century AD by the Roman Dioscorides; and... (Review)
Review
There is documentation of the use of opium derived products in the ancient history of the Assyrians: the Egyptians; in the sixth century AD by the Roman Dioscorides; and by Avicenna (980-1037). Reference to opium like products is made by Paracelsus and by Shakespeare. Charles Louis Derosne and Fredrich Wilhelm Adam Serturner isolated morphine from raw opium in 1802 and 1806 respectively, and it was Sertürner who named the substance morphine, after Morpheus, the Greek God of dreams. By the middle 1800s, Opium and related opioid derived products were the source of a major addiction in USA, and to some extent in the United Kingdom. Opioid products are of major therapeutic value in the treatment of pain from injury, post surgery, intractable pain conditions, and some forms of terminal cancer.
Topics: Humans; Analgesics, Opioid; Morphine; Narcotics; Opium
PubMed: 37515654
DOI: 10.1007/s10787-023-01304-y -
Journal of Pain and Symptom Management Sep 2023Pain is common among cancer patients. The evidence recommends using strong opioids in moderate to severe cancer pain. No conclusive evidence supports the effectiveness... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Pain is common among cancer patients. The evidence recommends using strong opioids in moderate to severe cancer pain. No conclusive evidence supports the effectiveness of adding acetaminophen to patients with cancer pain who are already using this regime.
OBJECTIVES
To assess the analgesic efficacy of acetaminophen in hospitalized cancer patients with moderate to severe pain receiving strong opioids.
METHODS
In this randomized blinded clinical trial, hospitalized cancer patients with moderate or severe acute pain managed with strong opioids were randomized to acetaminophen or placebo. The primary outcome was pain intensity difference between baseline and 48 hours using the Visual Numeric Rating Scales (VNRS). Secondary outcomes included change in morphine equivalent daily dose (MEDD), and patients' perception of improved pain control.
RESULTS
Among 112 randomized patients, 56 patients received placebo, 56 acetaminophen. Mean (standard deviation [SD]) decrease in pain intensity (VNRS) at 48 hours were 2.7 (2.5) and 2.3 (2.3), respectively (95% Confidence Interval (CI) [-0.49; 1.32]; P = 0.37). Mean (SD) change in MEDD was 13.9 (33.0) mg/day and 22.4 (57.7), respectively (95% CI [-9.24; 26.1]; P = 0.35). The proportion of patients perceiving pain control improvement after 48 hours was 82% in the placebo and 80% in the acetaminophen arms (P = 0.81).
CONCLUSION
Among patients with cancer pain on strong opioid regime, acetaminophen may not improve pain control, or decrease total opioid use. These results add to the current evidence available suggesting not to use acetaminophen as an adjuvant for advanced cancer patients with moderate to severe cancer pain who are on strong opioids.
Topics: Humans; Acetaminophen; Analgesics, Opioid; Analgesics, Non-Narcotic; Cancer Pain; Morphine; Acute Pain; Neoplasms; Double-Blind Method; Pain, Postoperative
PubMed: 37207788
DOI: 10.1016/j.jpainsymman.2023.05.002 -
The Lancet. Respiratory Medicine Apr 2024Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease, with most patients reporting cough. Currently, there are no proven treatments. We examined the use... (Randomized Controlled Trial)
Randomized Controlled Trial
Morphine for treatment of cough in idiopathic pulmonary fibrosis (PACIFY COUGH): a prospective, multicentre, randomised, double-blind, placebo-controlled, two-way crossover trial.
BACKGROUND
Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease, with most patients reporting cough. Currently, there are no proven treatments. We examined the use of low dose controlled-release morphine compared with placebo as an antitussive therapy in individuals with idiopathic pulmonary fibrosis.
METHODS
The PACIFY COUGH study is a phase 2, multicentre, randomised, double-blind, placebo-controlled, two-way crossover trial done in three specialist centres in the UK. Eligible patients aged 40-90 years had a diagnosis of idiopathic pulmonary fibrosis within 5 years, self-reported cough (lasting >8 weeks), and a cough visual analogue scale (VAS) score of 30 mm or higher. Patients were randomly assigned (1:1) to placebo twice daily or controlled-release morphine 5 mg orally twice daily for 14 days followed by crossover after a 7-day washout period. Patients were randomised sequentially to a sequence group defining the order in which morphine and placebo were to be given, according to a computer-generated schedule. Patients, investigators, study nurses, and pharmacy personnel were masked to treatment allocation. The primary endpoint was percentage change in objective awake cough frequency (coughs per h) from baseline as assessed by objective digital cough monitoring at day 14 of treatment in the intention-to-treat population, which included all randomised participants. Safety data were summarised for all patients who took at least one study drug and did not withdraw consent. This study was registered at ClinicalTrials.gov, NCT04429516, and has been completed.
FINDINGS
Between Dec 17, 2020, and March 21, 2023, 47 participants were assessed for eligibility and 44 were enrolled and randomly allocated to treatment. Mean age was 71 (SD 7·4) years, and 31 (70%) of 44 participants were male and 13 (30%) were female. Lung function was moderately impaired; mean forced vital capacity (FVC) was 2·7 L (SD 0·76), mean predicted FVC was 82% (17·3), and mean predicted diffusion capacity of carbon monoxide was 48% (10·9). Of the 44 patients who were randomised, 43 completed morphine treatment and 41 completed placebo treatment. In the intention-to-treat analysis, morphine reduced objective awake cough frequency by 39·4% (95% CI -54·4 to -19·4; p=0·0005) compared with placebo. Mean daytime cough frequency reduced from 21·6 (SE 1·2) coughs per h at baseline to 12·8 (1·2) coughs per h with morphine, whereas cough rates did not change with placebo (21·5 [SE 1·2] coughs per h to 20·6 [1·2] coughs per h). Overall treatment adherence was 98% in the morphine group and 98% in the placebo group. Adverse events were observed in 17 (40%) of 43 participants in the morphine group and six (14%) of 42 patients in the placebo group. The main side-effects of morphine were nausea (six [14%] of 43 participants) and constipation (nine [21%] of 43). One serious adverse event (death) occurred in the placebo group.
INTERPRETATION
In patients with cough related to idiopathic pulmonary fibrosis, low dose controlled-release morphine significantly reduced objective cough counts over 14 days compared with placebo. Morphine shows promise as an effective treatment to palliate cough in patients with idiopathic pulmonary fibrosis, and longer term studies should be the focus of future research.
FUNDING
The Jon Moulton Charity Trust.
Topics: Aged; Female; Humans; Male; Cough; Cross-Over Studies; Delayed-Action Preparations; Double-Blind Method; Idiopathic Pulmonary Fibrosis; Morphine Derivatives; Prospective Studies; Treatment Outcome; Middle Aged
PubMed: 38237620
DOI: 10.1016/S2213-2600(23)00432-0 -
Journal of Neuroscience Research Sep 2023As we all know, opioids are the drugs of choice for treating severe pain. However, very often, opioid use leads to tolerance, dependence, and hyperalgesia. Therefore,... (Review)
Review
As we all know, opioids are the drugs of choice for treating severe pain. However, very often, opioid use leads to tolerance, dependence, and hyperalgesia. Therefore, understanding the mechanisms underlying opioid tolerance and designing strategies for increasing the efficacy of opioids in chronic pain are important areas of research. Microglia are brain macrophages that remove debris and dead cells from the brain and participate in immune defense of the central nervous system during an insult or injury. However, recent studies indicate that microglial activation and generation of proinflammatory molecules (e.g., cytokines, nitric oxide, eicosanoids, etc.) in the brain may contribute to opioid tolerance and other side effects of opioid use. In this review, we will summarize the evidence and possible mechanisms by which proinflammatory molecules produced by activated microglia may antagonize the analgesic effect induced by opioids, and thus, lead to opioid tolerance. We will also delineate specific examples of studies that suggest therapeutic targets to counteract the development of tolerance clinically using suppressors of microglial inflammation.
Topics: Humans; Analgesics, Opioid; Microglia; Morphine; Drug Tolerance; Hyperalgesia; Inflammation
PubMed: 37186407
DOI: 10.1002/jnr.25199 -
The Journal of Pharmacology and... Nov 2023Awareness of drug interactions involving opioids is critical for patient treatment as they are common therapeutics used in numerous care settings, including both chronic... (Review)
Review
Awareness of drug interactions involving opioids is critical for patient treatment as they are common therapeutics used in numerous care settings, including both chronic and disease-related pain. Not only do opioids have narrow therapeutic indexes and are extensively used, but they have the potential to cause severe toxicity. Opioids are the classical pain treatment for patients who suffer from moderate to severe pain. More importantly, opioids are often prescribed in combination with multiple other drugs, especially in patient populations who typically are prescribed a large drug regimen. This review focuses on the current knowledge of common opioid drug-drug interactions (DDIs), focusing specifically on hydrocodone, oxycodone, and morphine DDIs. The DDIs covered in this review include pharmacokinetic DDI arising from enzyme inhibition or induction, primarily due to inhibition of cytochrome p450 enzymes (CYPs). However, opioids such as morphine are metabolized by uridine-5'-diphosphoglucuronosyltransferases (UGTs), principally UGT2B7, and glucuronidation is another important pathway for opioid-drug interactions. This review also covers several pharmacodynamic DDI studies as well as the basics of CYP and UGT metabolism, including detailed opioid metabolism and the potential involvement of metabolizing enzyme gene variation in DDI. Based upon the current literature, further studies are needed to fully investigate and describe the DDI potential with opioids in pain and related disease settings to improve clinical outcomes for patients. SIGNIFICANCE STATEMENT: A review of the literature focusing on drug-drug interactions involving opioids is important because they can be toxic and potentially lethal, occurring through pharmacodynamic interactions as well as pharmacokinetic interactions occurring through inhibition or induction of drug metabolism.
Topics: Humans; Analgesics, Opioid; Oxycodone; Hydrocodone; Pain; Drug Interactions; Morphine; Cytochrome P-450 Enzyme System
PubMed: 37679047
DOI: 10.1124/jpet.123.001651 -
Anesthesiology Jul 2023Balancing between opioid analgesia and respiratory depression continues to challenge clinicians in perioperative, emergency department, and other acute care settings.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Balancing between opioid analgesia and respiratory depression continues to challenge clinicians in perioperative, emergency department, and other acute care settings. Morphine and hydromorphone are postoperative analgesic standards. Nevertheless, their comparative effects and side effects, timing, and respective variabilities remain poorly understood. This study tested the hypothesis that IV morphine and hydromorphone differ in onset, magnitude, duration, and variability of analgesic and ventilatory effects.
METHODS
The authors conducted a randomized crossover study in healthy volunteers. Forty-two subjects received a 2-h IV infusion of hydromorphone (0.05 mg/kg) or morphine (0.2 mg/kg) 1 to 2 weeks apart. The authors measured arterial opioid concentrations, analgesia in response to heat pain (maximally tolerated temperature, and verbal analog pain scores at discrete preset temperatures to determine half-maximum temperature effect), dark-adapted pupil diameter and miosis, end-expired carbon dioxide, and respiratory rate for 12 h after dosing.
RESULTS
For morphine and hydromorphone, respectively, maximum miosis was less (3.9 [3.4 to 4.2] vs. 4.6 mm [4.0 to 5.0], P < 0.001; median and 25 to 75% quantiles) and occurred later (3.1 ± 0.9 vs. 2.3 ± 0.7 h after infusion start, P < 0.001; mean ± SD); maximum tolerated temperature was less (49 ± 2 vs. 50 ± 2°C, P < 0.001); verbal pain scores at end-infusion at the most informative stimulus (48.2°C) were 82 ± 4 and 59 ± 3 (P < 0.001); maximum end-expired CO2 was 47 (45 to 50) and 48 mmHg (46 to 51; P = 0.007) and occurred later (5.5 ± 2.8 vs. 3.0 ± 1.5 h after infusion start, P < 0.001); and respiratory nadir was 9 ± 1 and 11 ± 2 breaths/min (P < 0.001), and occurred at similar times. The area under the temperature tolerance-time curve was less for morphine (1.8 [0.0 to 4.4]) than hydromorphone (5.4°C-h [1.6 to 12.1] P < 0.001). Interindividual variability in clinical effects did not differ between opioids.
CONCLUSIONS
For morphine compared to hydromorphone, analgesia and analgesia relative to respiratory depression were less, onset of miosis and respiratory depression was later, and duration of respiratory depression was longer. For each opioid, timing of the various clinical effects was not coincident. Results may enable more rational opioid selection, and suggest hydromorphone may have a better clinical profile.
Topics: Humans; Hydromorphone; Morphine; Analgesics, Opioid; Cross-Over Studies; Healthy Volunteers; Pain; Drug-Related Side Effects and Adverse Reactions; Respiratory Insufficiency; Miosis; Pain, Postoperative; Double-Blind Method
PubMed: 37014986
DOI: 10.1097/ALN.0000000000004567 -
Ugeskrift For Laeger Jan 2024Chronic malignant pain is a common and feared condition. Especially, since many patients do not achieve proper pain relief from conventional peroral medication regimes... (Review)
Review
Chronic malignant pain is a common and feared condition. Especially, since many patients do not achieve proper pain relief from conventional peroral medication regimes and possible unacceptable side effects of high dosing. As argued in this review, in these patients, continuous intrathecal infusion of pain medicine by a programmable subcutaneously placed pump enables good pain relief, less systemic side effects, and better life quality. Intrathecal pain treatment should therefore be considered in patients with a proper performance score and suitable estimated life expectancy.
Topics: Humans; Morphine; Analgesics; Palliative Care; Pain Management; Pain; Chronic Pain
PubMed: 38305326
DOI: 10.61409/V08230541 -
Anaesthesia, Critical Care & Pain... Dec 2023
Topics: Pregnancy; Female; Humans; Morphine; Urination; Rosa; Analgesics, Opioid; Injections, Spinal; Pain, Postoperative; Anesthesia, Spinal; Double-Blind Method
PubMed: 37419322
DOI: 10.1016/j.accpm.2023.101272