When the pathophysiology of a medical condition is multimodal, ie, related to multiple physiological causes or mediated by multiple pathways, the optimal strategy can be to use a drug or a ...combination of drugs that contribute multiple mechanisms to the therapeutic endpoint. In such situations, a rational multimodal approach can also result in the fewest adverse effects. We discuss the quantitative analysis of multimodal action using the treatment of pain as a practical example and give examples of its application to some widely used analgesic drugs.
This article reviews the medical relevance of the quantitative evaluation of drug combinations, using pain and combinations of analgesics as specific examples. Such measure can help clinicians who seek to maximize therapeutic effect while simultaneously minimizing adverse effects.
History of Respiratory Stimulants Peppin, John F; Pergolizzi, Jr, Joseph V; Fudin, Jeffrey ...
Journal of pain research,
01/2021, Letnik:
14
Journal Article
Recenzirano
Odprti dostop
The interest in substances that stimulate respiration has waxed and waned throughout the years, intensifying following the introduction of a new class of drugs that causes respiratory depression, and ...diminishing when antidotes or better drug alternatives are found. Examples include the opioids--deaths increasing during overprescribing, diminishing with wider availability of the opioid receptor antagonist naloxone, increasing again during COVID-19; the barbiturates--until largely supplanted by the benzodiazepines; propofol; and other central nervous system depressants. Unfortunately, two new troubling phenomena force a reconsideration of the status-quo: (1) overdoses due to highly potent opioids such as fentanyl, and even more-potent licit and illicit fentanyl analogs, and (2) overdose due to polysubstance use (the combination of an opioid plus one or more non-opioid drug, such as a benzodiazepine, sedating antidepressant, skeletal muscle relaxant, or various other agents). Since these now represent the majority of cases, new solutions are again needed. An interest in respiratory stimulants has been revived. This interest can be informed by a short review of the history of this interesting class of medications. We present a short history of the trajectory of advances toward more selective and safer respiratory stimulants.
Summary
What is known and objective
When patients fail other treatment regimens and still suffer from pain sufficiently severe, opioid analgesics are appropriate and required. Unfortunately, ...constipation is a common adverse effect of opioids. Opioid‐induced constipation (OIC) can be treated with one of the new peripherally acting µ‐opioid receptor antagonist (PAMORA) agents. We summarize the mechanism of action of these drugs, with an emphasis on comparison of their potential for metabolic drug interactions.
Methods
Internet sources were searched for English‐language s related to the topic. Emphasis was placed on the mechanism of the PAMORAs, their metabolic pathways, drugs co‐administered with opioids and potential drug‐drug interactions (particularly at the level of CYP450 isozyme drug metabolism). Each source was evaluated and synthesized into the review.
Results and discussion
PAMORAs dose‐dependently antagonize the access of agonist molecules to opioid receptors, thereby directly eliminating or reducing OIC. But they differ from other opioid antagonists in that they are restricted to the periphery. Hence, they block constipation, but leave central opioid receptor‐mediated pain relief undiminished. The PAMORAs have similar efficacy and safety profiles, but many pain patients have comorbidities and thus are taking other medications, which increases the potential for metabolic drug interactions.
What is new and conclusion
Managing OIC in patients who have failed OTC or other therapies can be accomplished using a PAMORA, but healthcare providers must make prudent decisions that avoid or at least mitigate the potential for metabolic drug interactions in those patients with other comorbidities being managed medically by rational polypharmacy strategies.
Managing OIC in patients who have failed OTC or other therapies can be accomplished using a PAMORA, but healthcare providers must make prudent decisions that avoid or at least mitigate the potential for metabolic drug interactions in those patients with other comorbidities being managed medically by rational polypharmacy strategies.
Background/purpose Prescribing opioids for chronic noncancer pain has been strictly regulated for two decades in Taiwan. The aim of this study was to survey the patients' perspectives and potential ...drawbacks following long-term use of opioids. Methods An observational cross-sectional survey using the Taiwanese version of Brief Pain Inventory was conducted among outpatients with chronic noncancer pain registered by the Taiwan Food and Drug Administration. Patients were also asked about their sexual behavior, depression, opioid misuse behaviors, and use of complementary and alternative medicine. Results For 210 of 328 outpatients (64.0%), the median pain duration was 96 months and opioid treatment duration was 57 months. The median morphine equivalent dose was 150 mg/d, with 30.5% of patients exceeding the daily watchful dose, defined as 200 mg of morphine equivalent dose. Pain reduction after taking opioids was ∼50% in the past week. The top three diagnoses were chronic pancreatitis, spinal cord injury, and neuralgia. The leading side effects were constipation (46.7%), and decreased sexual desire (69.5%) and satisfaction (57.9%). Depression was currently diagnosed in 55.2% of patients. Twenty patients (9.5%) displayed at least one aberrant behavior in the past month. Only 76 (36.2%) patients had ever received nerve block procedures, and 118 (56.2%) tried complementary and alternative medicine. Conclusion This nationwide survey described the concurrent pain intensity, daily function, and various adverse effects by long-term opioids among 210 monitored outpatients with chronic noncancer pain in Taiwan. More efforts are suggested to reduce opioid prescriptions in the 30% of patients exceeding daily watchful dose.
Evidence from diverse sources suggests that persons who have a substance use disorder (SUD) often have problems with one or more additional substances, a situation broadly, if imprecisely, termed ...polysubstance use or more preferably multiple substance use disorder (mSUD). Because of the heavy toll of maladaptive neuronal dysregulation, morbidity, and mortality of SUDs, and increasingly of mSUD, on the individual, their families, the healthcare system, insurers, regulators, and society at large, it seems of value to have an estimate of the prevalence of mSUD. This turns out to be surprisingly difficult, due to nebulous or disparate definitions and to weaknesses in data acquisition methodology. We here attempt a pragmatic way of bracketing an estimate of mSUD prevalence in the US. We conclude that a reasonable estimated range of mSUD in the US is about 8 to 14 million persons. This approach provides a quick estimate for stakeholders involved in efforts to understand or deal with the immediate crisis of mSUD, as more refined estimations are pursued.
Abstract Sucrose produces physical dependence and reinforcing effects in rats. We hypothesized that similar effects could be demonstrated in planarians, the earliest animal with a centralized nervous ...system. We used two assays, one that quantifies withdrawal responses during drug absence as a reduction in motility and another that quantifies reinforcing effects using a conditioned place preference (CPP) design. In withdrawal experiments, planarians exposed to sucrose (1%) for 60 min and then tested in water for 5 min displayed reduced motility compared to water controls. Acute or continuous sucrose (1%) exposure did not affect motility. CPP experiments used a biased design to capitalize upon planarians' natural preference for the dark (pretest, sucrose conditioning in the light, posttest). Planarians conditioned with sucrose (1%) displayed a greater preference shift than sucrose-naïve planarians. Glucose (0.1, 1%), but not the non-digestible disaccharide lactulose (0.1, 1%), also produced a greater preference shift than water-exposed planarians. Development of sucrose-induced CPP was inhibited when sucrose (1%) conditioning was conducted in combination with dopamine receptor antagonists SCH 23390 (1 μM) or sulpiride (1 μM). These results suggest that the rewarding and reinforcing effects of sugar are highly conserved across species and that planarians offer an invertebrate model to provide insight into the pharmacological effects of sucrose and related sweeteners.
Could it be possible that we should give some weight to the contribution of biological differences as contributors to the greater fentanyl mortality in males than in females? Most current ...explanations for a sex difference are based largely on psychosocial and other non-physiologic contributions. Our recent findings suggest a biological contribution. This could have broad implications for the interpretation and prevention of fentanyl overdose deaths.
The venoms of the cone snail (
Conus) contain toxic peptides (conotoxins) that have remarkable selectivity for subtypes of a variety of mammalian voltage- and ligand-gated ion channels, G ...protein-coupled receptors, and neurotransmitter transporters. They thus have tremendous potential as pharmacologic tools. Less toxic analogs or mimetics could be highly-selective pharmacotherapeutic agents at their target sites. For this reason, conopeptides have been extensively studied and have progressed to clinical trials and even regulatory approval. However, the synthesis of the peptides remains difficult and stability and toxicity remain problems. A novel synthesis and testing of analogs incorporating diselenium bonds between selenocysteine residues in place of disulfide bonds between cysteine residues has recently been reported. The technique results in analogs that retain the folding of the native peptides, are more potent, and have the same or greater biological activity.
Tramadol is one of the most widely used centrally acting analgesics worldwide. Because of its multimodal analgesic mechanism (opioid plus nonopioid), the adverse effects profile of tramadol, similar ...to its analgesic profile, can be atypical compared with single-mechanism opioid analgesics. The comparison is often favorable (e.g., less respiratory depression or abuse), but it is sometimes cited as unfavorable in regard to seizure potential. As part of a broader study of this analgesic, we compared seizure induction in mice produced by administration of tramadol, the enantiomers and metabolites M1 (O-desmethyl tramadol), M2 (N-desmethyl tramadol), M3 (N,N-didesmethyl tramadol), M4 (O,N,N-tridesmethyl tramadol), and M5 (O,N-didesmethyl tramadol) of tramadol, and opioid and nonopioid reference compounds. We found that tramadol, its enantiomers, and M1 to M5 metabolites were of intermediate potency in this endpoint (on either a milligram per kilogram or millimole per kilogram basis). The SD50 (estimated dose required to induce seizures in 50% of test group) of tramadol to antinociceptive ED50 ratio was almost identical to that of codeine. The enantiomers of tramadol were about equipotent to tramadol on this endpoint. The M1 to M5 metabolites (and M1 enantiomers) of tramadol were less potent than tramadol. The relative potency of tramadol to opioids was not altered by quinidine (an inhibitor of CYP4502D6), noxious stimulus (48 degrees C hot-plate), multiple dosing, or in reserpinized mice. Tramadol seizures were increased by naloxone, principally at high tramadol doses and due to an effect on the (-)enantiomer that overcame the opposite effect on the (+)enantiomer. No synergistic effect on seizure induction was observed between concomitant tramadol and codeine or morphine.
e‐Cigarettes for smoking cessation: Do they deliver? Kitzen, Jan M.; McConaha, Jamie L.; Bookser, Megan L. ...
Journal of clinical pharmacy and therapeutics,
August 2019, Letnik:
44, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Summary
What is known and objective
Electronic nicotine delivery systems (ENDS) are battery‐powered devices that allow nicotine and/or other substances to be inhaled in aerosolized form. e‐Cigarettes ...(electronic cigarettes), the most commonly used ENDS, have been proposed to be smoking cessation aids. However, despite the rapid surge in their popularity, little is known about long‐term health consequences of e‐cigarette usage. We assess published data to see if they deliver what they promise.
Comment
e‐Cigarettes may contain uncertain quantities of various ingredients, and evidence of adulteration has been identified. Flavouring agents can alter the pharmacokinetics of nicotine and have uncertain impact on the nature of e‐cigarette use (eg ab initio use vs smoking cessation).
What is new and conclusion
Although e‐cigarettes have been proposed to be a safe approach to encouraging smoking cessation, there are inconsistencies in available data. And further data are needed regarding long‐term implications of primary and secondary exposure to e‐cigarette products.
Although e‐cigarettes have been proposed to be a safe approach to encouraging smoking cessation, there are inconsistencies in available data. And further data are needed regarding long‐term implications of primary and secondary exposure to e‐cigarette products.
PDF
