-
British Journal of Pharmacology Feb 2018Opioids may inhibit the 5-HT transporter (SERT) and the noradrenaline transporter (NET). NET inhibition may contribute to analgesia, and SERT inhibition or interactions...
BACKGROUND AND PURPOSE
Opioids may inhibit the 5-HT transporter (SERT) and the noradrenaline transporter (NET). NET inhibition may contribute to analgesia, and SERT inhibition or interactions with 5-HT receptors may cause serotonergic toxicity. However, the effects of different opioids on the human SERT, NET and 5-HT receptors have not been sufficiently studied.
EXPERIMENTAL APPROACH
We determined the potencies of different opioids to inhibit the SERT and NET in vitro using human transporter-transfected HEK293 cells. We also tested binding affinities at 5-HT , 5-HT and 5-HT receptors. Additionally, we assessed clinical cases of the serotonin syndrome associated with each opioid reported by PubMed and a World Health Organization database.
KEY RESULTS
Dextromethorphan, l(R)-methadone, racemic methadone, pethidine, tramadol and tapentadol inhibited the SERT at or close to observed drug plasma or estimated brain concentrations in patients. Tapentadol was the most potent NET inhibitor. Pethidine, tramadol, l(R)-methadone, racemic methadone, dextromethorphan and O-desmethyltramadol also inhibited the NET. 6-Monoacetylmorphine, buprenorphine, codeine, dihydrocodeine, heroin, hydrocodone, hydromorphone, morphine, oxycodone and oxymorphone did not inhibit the SERT or NET. Fentanyl interacted with 5-HT receptors and methadone, pethidine and fentanyl with 5-HT receptors, in the low micromolar range. Opioids most frequently associated with the serotonin syndrome are tramadol, fentanyl, tapentadol, oxycodone, methadone and dextromethorphan.
CONCLUSIONS AND IMPLICATIONS
Some synthetic opioids interact with the SERT and NET at potentially clinically relevant concentrations. SERT inhibition by tramadol, tapentadol, methadone, dextromethorphan and pethidine may contribute to the serotonin syndrome. Direct effects on 5-HT and/or 5-HT receptors could be involved with methadone and pethidine.
Topics: Analgesics, Opioid; HEK293 Cells; Humans; Norepinephrine Plasma Membrane Transport Proteins; Serotonin Plasma Membrane Transport Proteins; Serotonin Syndrome
PubMed: 29210063
DOI: 10.1111/bph.14105 -
The Cochrane Database of Systematic... Oct 2017Chronic pain is common and can be challenging to manage. Despite increased utilisation of opioids, the safety and efficacy of long-term use of these compounds for... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Chronic pain is common and can be challenging to manage. Despite increased utilisation of opioids, the safety and efficacy of long-term use of these compounds for chronic non-cancer pain (CNCP) remains controversial. This overview of Cochrane Reviews complements the overview entitled 'High-dose opioids for chronic non-cancer pain: an overview of Cochrane Reviews'.
OBJECTIVES
To provide an overview of the occurrence and nature of adverse events associated with any opioid agent (any dose, frequency, or route of administration) used on a medium- or long-term basis for the treatment of CNCP in adults.
METHODS
We searched the Cochrane Database of Systematic Reviews (the Cochrane Library) Issue 3, 2017 on 8 March 2017 to identify all Cochrane Reviews of studies of medium- or long-term opioid use (2 weeks or more) for CNCP in adults aged 18 and over. We assessed the quality of the reviews using the AMSTAR criteria (Assessing the Methodological Quality of Systematic Reviews) as adapted for Cochrane Overviews. We assessed the quality of the evidence for the outcomes using the GRADE framework.
MAIN RESULTS
We included a total of 16 reviews in our overview, of which 14 presented unique quantitative data. These 14 Cochrane Reviews investigated 14 different opioid agents that were administered for time periods of two weeks or longer. The longest study was 13 months in duration, with most in the 6- to 16-week range. The quality of the included reviews was high using AMSTAR criteria, with 11 reviews meeting all 10 criteria, and 5 of the reviews meeting 9 out of 10, not scoring a point for either duplicate study selection and data extraction, or searching for articles irrespective of language and publication type. The quality of the evidence for the generic adverse event outcomes according to GRADE ranged from very low to moderate, with risk of bias and imprecision being identified for the following generic adverse event outcomes: any adverse event, any serious adverse event, and withdrawals due to adverse events. A GRADE assessment of the quality of the evidence for specific adverse events led to a downgrading to very low- to moderate-quality evidence due to risk of bias, indirectness, and imprecision.We calculated the equivalent milligrams of morphine per 24 hours for each opioid studied (buprenorphine, codeine, dextropropoxyphene, dihydrocodeine, fentanyl, hydromorphone, levorphanol, methadone, morphine, oxycodone, oxymorphone, tapentadol, tilidine, and tramadol). In the 14 Cochrane Reviews providing unique quantitative data, there were 61 studies with a total of 18,679 randomised participants; 12 of these studies had a cross-over design with two to four arms and a total of 796 participants. Based on the 14 selected Cochrane Reviews, there was a significantly increased risk of experiencing any adverse event with opioids compared to placebo (risk ratio (RR) 1.42, 95% confidence interval (CI) 1.22 to 1.66) as well as with opioids compared to a non-opioid active pharmacological comparator, with a similar risk ratio (RR 1.21, 95% CI 1.10 to 1.33). There was also a significantly increased risk of experiencing a serious adverse event with opioids compared to placebo (RR 2.75, 95% CI 2.06 to 3.67). Furthermore, we found significantly increased risk ratios with opioids compared to placebo for a number of specific adverse events: constipation, dizziness, drowsiness, fatigue, hot flushes, increased sweating, nausea, pruritus, and vomiting.There was no data on any of the following prespecified adverse events of interest in any of the included reviews in this overview of Cochrane Reviews: addiction, cognitive dysfunction, depressive symptoms or mood disturbances, hypogonadism or other endocrine dysfunction, respiratory depression, sexual dysfunction, and sleep apnoea or sleep-disordered breathing. We found no data for adverse events analysed by sex or ethnicity.
AUTHORS' CONCLUSIONS
A number of adverse events, including serious adverse events, are associated with the medium- and long-term use of opioids for CNCP. The absolute event rate for any adverse event with opioids in trials using a placebo as comparison was 78%, with an absolute event rate of 7.5% for any serious adverse event. Based on the adverse events identified, clinically relevant benefit would need to be clearly demonstrated before long-term use could be considered in people with CNCP in clinical practice. A number of adverse events that we would have expected to occur with opioid use were not reported in the included Cochrane Reviews. Going forward, we recommend more rigorous identification and reporting of all adverse events in randomised controlled trials and systematic reviews on opioid therapy. The absence of data for many adverse events represents a serious limitation of the evidence on opioids. We also recommend extending study follow-up, as a latency of onset may exist for some adverse events.
Topics: Adult; Analgesics, Opioid; Chronic Pain; Humans; Patient Dropouts; Randomized Controlled Trials as Topic; Review Literature as Topic; Time Factors
PubMed: 29084357
DOI: 10.1002/14651858.CD012509.pub2 -
Pain Medicine (Malden, Mass.) Aug 2018Some crush-resistant tablet formulations (CRTs) reduce prescription opioid abuse by nonoral routes of administration (ROAs), especially insufflation and injection, while...
OBJECTIVE
Some crush-resistant tablet formulations (CRTs) reduce prescription opioid abuse by nonoral routes of administration (ROAs), especially insufflation and injection, while oral abuse increases. Oral abuse involving product manipulation vs swallowing whole for CRTs and comparators was examined.
METHODS
Abuse by oral modes of administration (e.g., swallowing whole, chewing, dissolving in the mouth), was examined using the ASI-MV, a computerized, clinical interview for adults in substance abuse treatment from January 2009 to March 2015. CRTs (reformulated oxycodone extended-release [ER], reformulated oxymorphone ER, and tapentadol ER) were compared with non-CRT versions, morphine ER, and oxycodone immediate-release single entity. Analyses employed descriptive statistics and logistic regression.
RESULTS
Among 364,329 unique assessments, 18,135 patients reported oral abuse of the CRTs and comparators examined. CRTs had a higher prevalence of oral abuse involving product manipulation than comparators (P < 0.0001) among all abusers of product. Oral abuse involving product manipulation for CRTs was greater among the subset of patients reporting oral abuse and significantly higher than comparators (P < 0.003). CRTs were significantly less likely than comparators to be swallowed whole (P < 0.0001) and significantly more likely to be chewed (P < 0.003). CRTs were more likely to be dissolved in the mouth than most comparators.
CONCLUSIONS
Results suggest the need for abuse-deterrent formulations designed to reduce abuse by oral administration with product manipulation, such as chewing. Advances in this area may reduce the overall abuse of prescription opioids and interrupt the progression from abuse by swallowing whole to oral administration involving product manipulation and other ROAs.
Topics: Administration, Oral; Adolescent; Adult; Analgesics, Opioid; Female; Humans; Male; Middle Aged; Opioid-Related Disorders; Tablets; Young Adult
PubMed: 29016905
DOI: 10.1093/pm/pnx151 -
Pain Dec 2017The mu opioid receptor (MOR) and metabotropic glutamate receptor 5 (mGluR5) are well-established pharmacological targets in the management of chronic pain. Both...
The mu opioid receptor (MOR) and metabotropic glutamate receptor 5 (mGluR5) are well-established pharmacological targets in the management of chronic pain. Both receptors are expressed in the spinal cord. MMG22, a bivalent ligand containing 2 pharmacophores separated by 22 atoms, which simultaneously activates MOR and antagonizes mGluR5, has been shown to produce potent reversal of tactile hypersensitivity in rodent models of lipopolysaccharide (LPS)-and bone cancer-induced chronic pain. This study assessed whether intrathecal MMG22 also is effective in reducing pain of neuropathic origin. Furthermore, we theorized that MMG22 should reduce hyperalgesia in nerve-injured mice in a manner consistent with a synergistic interaction between MOR and mGluR5. Several weeks after spared nerve injury, tactile hypersensitivity was reversed in mice by the intrathecal injection of MMG22 (0.01-10 nmol) but also by its shorter spacer analog, MMG10, with similar potency. The potencies of the bivalent ligands were 10- to 14-fold higher than those of the compounds upon which the bivalent structure was based, the MOR agonist oxymorphone and the mGluR5 antagonist MPEP. Coadministration of oxymorphone and MPEP demonstrated analgesic synergism, an interaction confirmed by isobolographic analysis. This study indicates that in the spared nerve injury-induced model of neuropathic pain, the 2 pharmacophores of the bivalent ligands MMG22 and MMG10 target MOR and mGluR5 as separate receptor monomers. The observed increase in the potency of MMG22 and MMG10, compared with oxymorphone and MPEP, may reflect the synergistic interaction of the 2 pharmacophores of the bivalent ligand acting at their respective separate receptor monomers.
Topics: Analgesics; Animals; Hyperalgesia; Injections, Spinal; Ligands; Male; Mice; Narcotic Antagonists; Neuralgia; Receptor, Metabotropic Glutamate 5; Receptors, Opioid, mu
PubMed: 28891868
DOI: 10.1097/j.pain.0000000000001050 -
Journal of Ayub Medical College,... 2017Atypical Haemolytic Uremic Syndrome (aHUS) is a rare life threatening entity characterized by thrombocytopenia, haemolytic anaemia and renal dysfunction. It is a...
Atypical Haemolytic Uremic Syndrome (aHUS) is a rare life threatening entity characterized by thrombocytopenia, haemolytic anaemia and renal dysfunction. It is a thrombotic microangiopathy related to genetic mutations in the alternate complement pathway and has a distinct pathophysiology which makes it harder to distinguish from other microangiopathies. We present a case of a 25-year-old male patient with history of polysubstance abuse who presented with chest pain and dyspnoea. He admitted to using injectable oxymorphone (Opana) two weeks before presentation. Patient's vital signs were stable except for tachycardia and high blood pressure. On physical examination, epigastric tenderness and mild splenomegaly was appreciated. Urine Drug Screen was positive for oxycodone and opiates. Laboratory work up revealed haemolytic anaemia, thrombocytopenia and acute kidney injury. Extensive evaluation resulted in our impression of the disease being atypical haemolytic-uremic syndrome. He was managed with dialysis, intravenous steroids and plasmapheresis with improvement in his hematologic parameters.
Topics: Adult; Analgesics, Opioid; Atypical Hemolytic Uremic Syndrome; Humans; Male; Oxymorphone; Renal Dialysis; Thrombotic Microangiopathies
PubMed: 28718268
DOI: No ID Found -
BMJ Case Reports Jul 2017We describe the case of a 35-year-old man presenting with thrombotic microangiopathy (TMA) and renal impairment following, as he later disclosed, intravenous injection...
We describe the case of a 35-year-old man presenting with thrombotic microangiopathy (TMA) and renal impairment following, as he later disclosed, intravenous injection of oral formulation tamper-resistant extended-release oxycodone hydrochloride (Oxycontin). Recurrent misuse of this agent was associated with relapsing TMA despite treatment with terminal complement inhibitor eculizumab. Cases of TMA have been reported in the USA in association with intravenous misuse of extended-release oxymorphone (Opana ER) after the introduction of a new non-crushable formulation in 2012. There are two reported accounts of TMA associated with tamper-resistant Oxycontin, which became available in Australia in 2014. This is the first documented case in which eculizumab was used. This case illustrates the practical diagnostic challenges in identifying TMA disorders, and the importance of a detailed drug history. It also highlights the need to clarify what role, if any, eculizumab therapy has in cases of drug-associated TMA.
Topics: Adult; Analgesics, Opioid; Antibodies, Monoclonal, Humanized; Complement Inactivating Agents; Delayed-Action Preparations; Humans; Injections, Intravenous; Male; Opioid-Related Disorders; Oxycodone; Oxymorphone; Renal Insufficiency; Substance Abuse, Intravenous; Thrombotic Microangiopathies
PubMed: 28716778
DOI: 10.1136/bcr-2017-220977 -
Case Reports in Hematology 2017Opana ER (oxymorphone) is an opioid drug available throughout the United States, and intravenous abuse of the crushed oral formulation has been associated with...
Opana ER (oxymorphone) is an opioid drug available throughout the United States, and intravenous abuse of the crushed oral formulation has been associated with drug-induced thrombotic microangiopathy. In this abstract, we describe two young patients who lived together and used Opana ER intravenously. Both presented with microangiopathic hemolytic anemia that mimicked thrombotic thrombocytopenic purpura (TTP). Treating this condition poses a clinical challenge, as it is difficult to distinguish it from TTP. The role for plasma exchange is not clear but can be used while awaiting the results of the ADAMTS-13 activity, but ultimately supportive care with drug discontinuation is the recommended therapy of choice. Patients should be counseled against Opana ER's intravenous use, and users should be offered drug rehabilitation therapy.
PubMed: 28607779
DOI: 10.1155/2017/1623907 -
Oxford Medical Case Reports Jun 2017Opana (oxymorphone) is a powerful semi-synthetic opioid agonist used for chronic pain management that is ingested orally. However, improper injection of Opana can lead...
Opana (oxymorphone) is a powerful semi-synthetic opioid agonist used for chronic pain management that is ingested orally. However, improper injection of Opana can lead to a rare and fatal blood disorder known as thrombotic microangiopathy. Opana-induced thrombotic microangiopathy can be easily mistaken for thrombotic thrombocytopenic purpura (TTP), leading to the initiation of therapeutic plasma exchange. Current literature has conflicting views on the necessity of therapeutic plasma exchange for the treatment of Opana-induced thrombotic microangiopathy. In our case report, a 47-year-old Caucasian male was admitted with a presentation suspicious for TTP then underwent therapeutic plasma exchange without clinical improvement. With supportive treatment only, the patient eventually improved and later admitted to intravenously abusing oral Opana 1-2 days prior to becoming ill.
PubMed: 28580158
DOI: 10.1093/omcr/omx026 -
Drugs in R&D Sep 2017Oxycodone is a semisynthetic opioid used for the treatment of moderate to severe pain. Two separate studies were conducted to assess the pharmacokinetic bioequivalence... (Comparative Study)
Comparative Study Randomized Controlled Trial
Pharmacokinetic Bioequivalence Studies of an Extended-Release Oxycodone Hydrochloride Tablet in Healthy Japanese Subjects Under Fasting and Fed Conditions Without an Opioid Antagonist.
Oxycodone is a semisynthetic opioid used for the treatment of moderate to severe pain. Two separate studies were conducted to assess the pharmacokinetic bioequivalence of a newly formulated oxycodone hydrochloride extended-release tablet to a marketed oxycodone product in Japan under fasting and fed conditions. Each study was a randomized, open-label, single-dose, single-center, two-period, two-way crossover study. Healthy male Japanese subjects received the oxycodone 10-mg products under fasting and fed conditions. Blood samples were collected at specified time intervals, and plasma concentrations of oxycodone were analyzed using a validated liquid chromatography tandem mass spectrometry assay method. The pharmacokinetic parameters were determined via non-compartmental analysis. Pharmacokinetic metrics used for bioequivalence assessment were the maximum observed plasma concentration (C ) and the area under the concentration-time curve up to the last sampling time (AUC ). A total of 24 healthy subjects were enrolled in each study. One subject withdrew after completion of the first sequence under fed conditions. The ratios of geometric least square means for C and AUC under fasting conditions were 1.1110 (90% confidence interval [CI] 1.0562-1.1687) and 0.9946 (90% CI 0.9670-1.0231), respectively. The ratios of geometric least square means for C and AUC under fed conditions were 1.1417 (90% CI 1.0959-1.1895) and 1.0135 (90% CI 0.9810-1.0470), respectively. The 90% CIs were within the predefined range (0.80-1.25). Both treatments were well tolerated when taken without an opioid antagonist in healthy Japanese subjects. Pharmacokinetic bioequivalence between test and reference formulations under fasting and fed conditions was concluded in terms of both rate and extent of absorption.
Topics: Adult; Analgesics, Opioid; Area Under Curve; Chromatography, Liquid; Cross-Over Studies; Delayed-Action Preparations; Fasting; Food-Drug Interactions; Humans; Japan; Male; Oxycodone; Tablets; Tandem Mass Spectrometry; Therapeutic Equivalency; Young Adult
PubMed: 28516342
DOI: 10.1007/s40268-017-0184-x -
Pharmacogenomics Mar 2017Oxycodone is partly metabolized to the active metabolite oxymorphone by hepatic CYP2D6 in the liver. Significant genetic variability in CYP2D6 activity affects... (Observational Study)
Observational Study
AIM
Oxycodone is partly metabolized to the active metabolite oxymorphone by hepatic CYP2D6 in the liver. Significant genetic variability in CYP2D6 activity affects oxymorphone formation. This study aimed to associate CYP2D6 genotype and oxycodone's metabolism.
METHODS
30 children were administered oral oxycodone postoperatively. Plasma levels of oxycodone and oxymorphone, and CYP2D6 genotype were analyzed. CYP2D6 genotype and oxycodone metabolism phenotype were determined based on CYP2D6 total activity score (TAS) and metabolism phenotype: poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM) or ultrarapid metabolizer (UM).
RESULTS
Compared with PM/IM subjects, significantly greater oxymorphone exposure was seen in EM subjects (p = 0.02 for C, p = 0.016 for AUC and p = 0.026 for AUC). Similarly, higher TAS value was found to be associated with greater oxymorphone exposure. Higher conversion of oxycodone to oxymorphone was observed in EM subjects compared with PM/IM subjects (p = 0.0007 for C, p = 0.001 for AUC and p = 0.004 for AUC).
CONCLUSION
CYP2D6 phenotypes explain metabolism of oxycodone in children, and oxymorphone exposure is higher in CYP2D6 EM phenotype. Further studies are needed to predict the occurrence of adverse event and tailor oxycodone dose for a specific CYP2D6 phenotype.
Topics: Administration, Oral; Adolescent; Analgesics, Opioid; Child; Child, Preschool; Cytochrome P-450 CYP2D6; Female; Humans; Male; Oxycodone; Pain, Postoperative; Pharmacogenetics; Pilot Projects; Prospective Studies
PubMed: 28244808
DOI: 10.2217/pgs-2016-0183