Identification of a novel opioid, N-piperidinyl etonitazene (etonitazepipne), in patients with suspected opioid overdose.

BACKGROUND: Novel opioids in the illicit drug supply, such as the "nitazene" group of synthetic opioids, present an ongoing public health problem due to high potency and respiratory depressant effects. We describe three patients in whom N-piperidinyl etonitazene, a compound not previously reported in human exposure, was detected after suspected opioid overdose. Other substances that these patients tested for included fentanyl, cocaine, levamisole, phenacetin, benzoylecgonine, para-fluorofentanyl, presumptive heroin (tested as 6-monoacetylmorphine (6-MAM), morphine, and codeine), and tramadol. METHODS: This is a case series of patients with acute opioid overdose enrolled in an ongoing multicenter prospective cohort study. Data collected included reported substance use, clinical course, naloxone dose and response, outcome, and analytes detected in biological samples. RESULTS: Between October 6, 2020 and October 31, 2021, 1006 patients were screened and 412 met inclusion criteria. Of these, three patients (age 33-55) tested positive for N-piperidinyl etonitazene at one site in New Jersey over a period of three days in July 2021. Two patients reported the use of cocaine; one reported the use of heroin and alprazolam. All three patients received naloxone with improvement in their mental status (2 milligrams (mg) intranasally (IN); 8 mg IN; 0.08 mg intravenous (IV)). Two of three received subsequent doses for recurrence of opioid toxicity (0.4-0.6 mg IV). One patient was diagnosed with pneumonia and admitted to the intensive care unit, one was discharged from the Emergency Department (ED), and one used additional drug while in the ED and required admission for a naloxone infusion. None developed organ damage or sequelae. CONCLUSION: These cases represent a local outbreak of a novel "nitazene" opioid. Public health toxicosurveillance should incorporate routine testing of this emerging class of synthetic compounds in the illicit drug supply.

Microspherical Particles of Solid Dispersion of Polyvinylpyrrolidone K29-32 for Inhalation Administration.

Inhalation administration is a promising alternative to the invasive drug delivery methods. The particle size required for ideal drug aerosol preparation is between 1 and 3 µm. The application of microspherical particles of solid dispersions enhances bioavailability of poorly soluble drugs due to the solubilization. In the present work, the spray drying process of the production of microspherical particles of solid dispersions of polyvinylpyrrolidone K29-32 with model hydrophobic drug, phenacetin, was optimized using the results of DSC, PXRD, and viscometry. The diameter of the obtained particles is within 1-3 µm range. The Gibbs energy of dissolution in water was shown to be negative for the mixture with polymer/phenacetin mass ratio 5 : 1. We have demonstrated that the optimal size distribution for the inhalation administration is obtained for microspherical particles produced using spray caps with 7.0 µm hole size. The dissolution rates of phenacetin from the produced microspherical particles were faster than that of drug powder. As evidenced by powder X-ray diffraction data, phenacetin stayed in amorphous state for 4 months in microspherical particles of solid dispersions. According to the obtained results, strategic application of the spray drying process could be beneficial for the improvement of the pharmaceutical properties of model drug, phenacetin.

Bladder tumor associated with phenacetin abuse: a case report and a review of the literature.

We herein report the case of a bladder tumor in an 85-year-old man who had been engaged in phenacetin abuse. He had been taking phenacetin owing to migraine headaches since he was 45 year of age. His total intake of phenacetin was approximately 7.3 to 11.5 kg over a period of years. He visited the Department of Urology in our hospital due to gross hematuria and pain on urination. IVP and a pelvic CT scan revealed a tumor mass on the right lateral wall of the urinary bladder. TUR-BT was performed. A histopathological examination of the resected specimen was diagnosed as urotherial carcinoma, grade 2∼3, pT2N0M0. To our acknowledge, only 24 cases of urotherial tumors owing to phenacetin abuse have been previously reported in the Japanese literature, making this the 25 th such case to be reported in Japan.

[Novel potential uses of thalidomide in the management of pain? A review of the literature]. / Neue Indikation für Thalidomid in der Schmerztherapie. Eine Literaturübersicht.

Thalidomide was introduced as a sedative and antiemetic agent to the European market in the late 1950s. However, it soon became clear that a hitherto unheard-of incidence of severe birth defects was due to the maternal use of thalidomide and the drug was withdrawn from the market. Despite its teratogenesis, thalidomide is currently being rediscovered because of its known spectrum of anticachectic, antiemetic, mildly hypnotic, anxiolytic, anti-inflammatory, antiangiogenic, and analgesic properties. The mechanism of action of thalidomide is probably based on its immunomodulatory effect, namely the suppression of production of tumor necrosis factor alpha and the modulation of interleukins. A striking but not well-known finding is the effectiveness of thalidomide as an analgesic or analgesic adjuvant. During the early era of thalidomide use, the drug was shown to enhance the analgesic efficacy of a combined treatment with acetylsalicylic acid, phenacetin, and caffeine (APC) by testing "normal volunteers, using electrical stimulation of teeth." The combination of thalidomide and APC was superior to other combinations (APC alone, APC and codeine) with respect to both the total analgesic effect and the duration of this analgesic effect. In 1965 thalidomide was found to be effective in treating the painful subcutaneous manifestations of the leprosy-associated erythema nodosum leprosum, a condition for which it eventually was approved by the United States Food and Drug Administration in 1998. In an animal model of neuropathic pain (chronic constriction injury), thalidomide was shown to reduce both mechanical allodynia and thermal hyperalgesia. Recent studies documented the analgesic efficacy of thalidomide in treating painful mucocutaneous aphthous ulcers associated with HIV syndrome and Behcet's disease.However, to date there are no recent clinical trials that are specifically designed to explore the analgesic potential of thalidomide. In view of the current basic research and clinical findings,we suggest to investigate the potential benefits of thalidomide in severe pain conditions that respond poorly to common pain management approaches such as neuropathic pain, postherpetic neuralgia, or central pain phenomena. Because its mechanism of action is distinct from that of other drugs such as steroids, thalidomide offers the possibility of a combined treatment with other agents with nonoverlapping toxicities. We conclude that thalidomide, when used properly,may enrich the therapeutic regimen in the management of some pain-related conditions.

Use of analgesics in self-medication.

Self-medication with analgesics is common and accepted and even recommended by health systems in order to avoid reimbursement. Self-medication, nevertheless, is not an easy task, since making choices is difficult for patients on the basis of the available standard information. Guiding information for patients has to be improved, but also physicians need to be trained how to handle self-medication of their patients. Special attention should be paid to the approval of combination analgesics for the treatment of headache and migraine. There were two major points of discussion during the last decades: possible risks of nephropathy and possible drug-induced overuse. According to a very recent evaluation, analgesic-associated nephropathy appears to have been primarily caused by phenacetin rather than any other single or combination analgesics. Analgesic-induced overuse is also caused by the psychotropic actions of phenacetin in presentations providing rapid absorption, such as powders, rather than by other analgesics or caffeine.

The onset of action and the analgesic efficacy of Saridon (a propyphenazone/paracetamol/ caffeine combination) in comparison with paracetamol, ibuprofen, aspirin and placebo (pooled statistical analysis).

The objective was to evaluate the onset of action, analgesic efficacy and tolerability of Saridon*, a propyphenazone 150 mg/paracetamol 250 mg/caffeine 50 mg combination, in comparison with paracetamol 500 mg, aspirin 500 mg, ibuprofen 200 mg and placebo, by a pooled statistical analysis of eight studies. Out of 500 generally healthy patients (55.2% men, 44.8% women), average age 43.5 years, 329 (65.8%) had moderate and 171 (34.2%) severe acute dentoalveolar pain. More Saridon-treated patients reported 'pain gone/partly gone' and less 'pain unchanged or worse' compared with paracetamol, aspirin and placebo 30min (p = 0.009, p < 0.001, p = 0.001, respectively) and 60 min after dosing (p < 0.0001 for all). The difference with ibuprofen was observed 60 min after dosing (p < 0.01). Pain intensity differences 30 min and 60 min after dosing infer that Saridon has a faster onset of action than all of the other medications that it was compared with (ibuprofen at only 60 min after dosing). Total pain relief scores four hours after dosing were higher in the Saridon group compared with the paracetamol, ibuprofen, placebo (p < 0.0001 for all) and aspirin groups (p < 0.01). At the end of the study, patients assessed Saridon as more efficacious than the other study medications (p < 0.0001 for all). No serious adverse events were observed with any of the drugs studied. All medications were well tolerated. Twenty patients (4.0%) reported adverse events with no significant differences between groups. The most common adverse events were gastrointestinal disorders, followed by nervous system, skin, subcutaneous tissue, respiratory, cardiac and general disorders. Saridon is an effective analgesic that combines the advantage of fast onset and effective analgesia as compared with paracetamol alone, ibuprofen, aspirin or placebo. The results of this pooled analysis of eight studies should be confirmed in a double-blind study, since seven of the studies included in this analysis were single blind.

Drug-induced hepatitis with hepatic granuloma due to saridon.

A 38-year-old Japanese woman with no past history of liver disease developed liver dysfunction associated with fever, anorexia, and general malaise following the prolonged administration of saridon. A liver biopsy demonstrated multiple noncaseating epithelioid granulomas within hepatic lobules, with an inflammatory cell infiltrate of the lobular parenchyma and portal tracts. Viral markers and autoantibodies were negative. Lymphocyte stimulation tests for saridon and for isopropylantipyrine, one of the constituents of saridon, were positive, and therefore a diagnosis of drug-induced hepatitis due to administration of saridon was made. Her symptoms resolved and liver function test results returned to normal following discontinuation of the drug. The possibility of drug-induced hepatitis must be considered when liver dysfunction or systemic symptomatology develops during saridon therapy.

[Comparative study of the analgesic effect of Dikalm and Saridon in headaches of various causes]. / Uporedno ispitivanje analgetskog efekta Dikalma i Saridona u slucaju glavobolja razlicitog porekla.

Headache, as a syndrome, represents large health and wider socio-economic problem in every community for its massive occurrence and frequent absence of therapeutic response to the administered analgesics. That is why the finding, and later production of the drug that would satisfy the criteria of analgesic, efficacious in the treatment of headache, without the entering in etiology of syndrome are presented as the imperative. In connection with that was set the aim of the investigation: to investigate comparative analgesic efficacity of new preparation--Dikalm compared to analgesic that was for a long time present in our pharmaceutic market--Saridon tablets in the patients with different neurologic diseases, where headache represents the leading symptom of their difficulties. The investigation included 30 patients--10 patients were cross-examined with the use of both preparations in the treatment of headache episodes that appeared in separate time interval, and 20 patients received one another preparation. The headache intensity, residual headache, adverse effects and the need for repeating were graded by original standardized scales. The results of investigation revealed significantly better analgesic effect of therapeutic combination contained in Dikalm preparation, as for persistent, residual headache, as for the need of repeating the analgesics administration, what was specially pronounced in the group that cross-received both preparations, or in the whole group compared to the therapeutic combination contained in Saridon tablets. It was concluded that Dikalm represented the drug with efficacious analgesic and with minimal adverse effects.

End-stage renal failure due to analgesic nephropathy, its changing pattern and cardiovascular mortality. EDTA-ERA Registry Committee.

The changing pattern of prevalence and age distribution of analgesic nephropathy as a cause of end-stage renal failure (ESRF) in patients on RRT was analysed using the EDTA-ERA Registry's files. Comparing 1990 to 1981, the percentage of patients with analgesic nephropathy decreased in many European countries and the Registry's average came down from 3 to 2%. The highest prevalence was noted for Switzerland, which showed a decrease from 28 in 1981 to 12% in 1990. During the same interval the age distribution shifted to the right with an increase in median age from 57 to 63 at start of RRT for analgesic nephropathy. In Switzerland the age-specific acceptance rate to RRT for patients with analgesic nephropathy decreased to less than 1/3 in the age cohorts below 55 but increased in those aged 65 or older. This increase in the elderly cohorts appeared to be related to the growing acceptance rate to RRT of elderly patients in general rather than to an increasing incidence of ESRF due to analgesic nephropathy. Mortality in general and death rates due to cardiovascular causes were found not to differ in RRT patients with analgesic nephropathy from that of other standard primary renal diseases (excluding diabetic nephropathy and systemic diseases). Some 20 years after withdrawal of phenacetin from the analgesic market, analgesic nephropathy all but disappeared as a cause of ESRF in Sweden and Denmark, and the same may be expected to occur in countries like Switzerland, Belgium, and others in the not too far distant future.

[Study of the association of bladder cancer and phenacetin use. Problems set by a pharmaco-epidemiological study]. / Etude de l'association entre le cancer de la vessie et la consommation de phénacétine. Problèmes posés par une étude de pharmacoépidémiologie.

In a survey of the literature, phenacetin appears to be responsible for an increased risk of urothelial tumours in humans, especially renal pelvis tumour. Few observations have suggested an association between bladder cancer and phenacetin containing analgesics however. To assess this association in France, a case-control study of bladder cancer (143 cases, 120 controls) was undertaken. We point at some methodological difficulties, such as difficulties of recall, definition of a control group, non-responses, possible French distinctive features of analgesics use. Results are not able to confirm the suspected relationship between bladder cancer and phenacetin use.

[Analgesics and antipyretics in pediatrics]. / Analgetika-antipyretika v pediatrických indikacích.

We compared the most usual analgetics-antipyretics in pediatric indications, especially paracetamol and acetylosalicylic acid. We watched the effectivity and side effects of both substances according to literature.

Fiorinal with codeine in the treatment of tension headache--the contribution of components to the combination drug.

The contribution of the Fiorinal and codeine phosphate components to the effectiveness of the Fiorinal with Codeine combination in the treatment of tension headache symptoms was evaluated in a randomized, placebo-controlled, multicenter double-blind study. Patients admitted to the trial took two capsules of Fiorinal with Codeine, Fiorinal alone, codeine alone, or placebo during each of two tension headache attacks. Immediately before and at intervals up to four hours after drug ingestion, patients rated pain severity, pain relief, the tense and uptight feeling, and muscle stiffness. The response to treatment was evaluated in 154 patients. Despite a high placebo response, a factor known to obscure the contribution of components, Fiorinal and codeine were each found to contribute significantly to the therapeutic effect of the Fiorinal with Codeine combination. Statistical or borderline superiority of the combination drug over Fiorinal alone was seen most frequently at the early evaluations, a finding that reflected the rapid onset of action of codeine. Statistically significant differences between Fiorinal with Codeine and codeine alone seen principally at the later assessments reflected the long duration of action of the Fiorinal component. The frequency of adverse reactions did not differ significantly among the four study groups.

Fiorinal with Codeine in the management of tension headache: impact of placebo response.

The well-known difficulty in distinguishing the response to a combination headache medication and its individual components in the presence of a high placebo response was again demonstrated in a randomized, double-blind, placebo-controlled, multi-center trial comparing Fiorinal with Codeine and its Fiorinal and codeine phosphate components in relieving the pain, tension, and muscle contraction associated with tension headache. In the original analysis of the study data, no distinction was apparent between patient response to Fiorinal with Codeine and the response to the individual components, a finding that appeared to conflict with the results of a similar earlier study. This apparent discrepancy was attributable to a high placebo response in the later study. Separation of study subjects according to their baseline level of anxiety and pain identified a subset of less anxious patients with mild to moderate pain severity who were least likely to respond to placebo. Analysis of data from these patients showed that Fiorinal with Codeine was significantly better than placebo in improving patients' self-ratings of various symptoms of tension headache at 0.5, 1, 2, 3, and 4 hours after ingestion of the study medication. The combination drug was also consistently superior to Fiorinal alone and codeine alone in improving the patients' self-evaluation items, and differences between the combination and its components were generally of statistical or borderline significance during the last half of the study. The investigators' assessments of the effect of treatment on the three principal variables in tension headache (namely, headache pain, psychic tension, and muscle contraction of the head, neck, and shoulders) at the final patient visit also showed Fiorinal with Codeine to be not only significantly superior to placebo but also consistently superior to either component. The superiority of the combination over Fiorinal alone achieved borderline significance for headache pain and psychic tension.

Analgesic use by leprosy patients.

We questioned 235 subjects with leprosy regarding the consumption of analgesic preparations, and 46 subjects (19.5%) admitted to having consumed more than 2 kg of analgesics; the main reason for consumption was neuritic pain. The commonly consumed analgesics are paracetamol (acetaminophen) and local proprietary compound analgesics containing aspirin, phenacetin, and caffeine. Intravenous urograms were done on 28 of the 46 subjects, but none showed evidence of renal papillary necrosis. The reasons for this lack of renal papillary necrosis are postulated. Excessive ingestion of analgesics may be a contributory factor in the development of interstitial nephritis in patients with leprosy.