Immunoprotective therapy of suppression of humoral immune response, pain induced (search for narcotic analgesics with immunoprotective activity)

Problematic issues of prevention of humoral immune response suppression induced by pain in conditions of the experimental model of severe mechanical trauma are highlighted. It has been established that one of the pathogenetic factors of trauma depressing the humoral immune response is pain. Thus, drugs inhibiting intra-central transmission of afferent impulse, and, in particular, narcotic analgesics, may be considered as drugs with immunoprotective activity. Evaluation of the immunoprotective activity of five narcotic analgesics administered immediately after trauma to immunized mice in the first 24 hours of post-traumatic period showed the presence of the estimated effect in morphine hydrochloride, fentanyl and pifurben. By 106 splenocytes of mice received these preparations and immunized on the first day after the trauma, reliably more antibodies forming cells are formed in mice in comparison with their number in animals received after the trauma as narcotic analgesics intermediol and dipidolor. Thus, morphine hydrochloride, fentanyl and pifurben, i.e. drug analgesics with immunoprotective activity, should be considered as the preferred drugs in the group of narcotic analgesics in emergency care for patients with severe trauma. The use of narcotic analgesics with immunoprotective properties should be considered as one of the measures in the complex of measures aimed at the prevention of post-traumatic immunodeficiency and infection in an immunocompromised host. Infections are difficult to diagnose and often with an unfavorable outcome.

The Study of Pharmacokinetics Parameters of Morphine Hydrochloride, Long-acting Tablets in Cancer Patients with Severe Chronic Pain Syndrome

Introduction. Effective drug therapy for cancer patients with chronic pain syndrome (CPS) of high intensity is one of the priorities of modern healthcare. Currently, non-narcotic and narcotic analgesics are used for pain relief according to a three-steps scheme. In the absence of contraindications, it is preferable to prescribe medications per os and prolonged forms, which will allow the patient to maintain selfcare and comfort.Aim. To study the pharmacokinetic properties of a drug with a prolonged mechanism of action «Morphine hydrochloride», in a film-coated tablet formof a dosage 30 mg, in cancer patients with severe CPS.Materials and methods. For the analysis of the pharmacokinetics of the studied drug after single and multiple doses of 20 patients who received 10- day analgesic therapy with the studied drug «Morphine hydrochloride», long-acting film-coated 30 mgtablets. manufacturer FSUE Moscow Endocrine Plant, Russia. Route of administration: per os. The study duration was 17 days: screening duration up to 7 days; duration of therapy up to 10 days.Results and discussion. The concentration of morphine in plasma was determined by HPLC-tandem mass spectrometry, within 12 hours after taking the study drug (1 of long-acting, film-coated tablet 30 mg). The following pharmacokinetic parameters were obtained on Day 5: T1/2 – 6.08 ± 4.37 hours and 14.46 ± 30.86 hours, Tmax – 2.5 ± 1.86 hours, Cmax – 43.91 ± 27.24 ng/ml. Values of pharmacokinetic parameters averaged over all days are presented. It was found that T1/2 for the studied drug T1/2 is 9.21 ± 14.94 hours, Tmax 2.87 ± 2.36 hours. The average maximum concentration (Cmax) on the day of the study drug was 36.52 ng/ml.Conclusion. As a result of the study of pharmacokinetics, it was found that the drug «Morphine hydrochloride», long-acting tablets film-coated with a of 30 mg was found in serum after oral administration after 15 minutes and reaches a maximum concentration in the blood in 3 hours, the half-life is on average 9 hours, the maximum concentration is 36.52 ng/ml.

Measurement of mechanical withdrawal threshold on full-thickness cutaneous wounds in rats using the von Frey test

Objective: A method for measuring mechanical withdrawal threshold of full-thickness cutaneous wound pain in animal models is lacking. This study aimed to confirm the validity and reactivity of the von Frey test in full-thickness cutaneous wounds in rats. Method: A 1.5cm-diameter wound was established on the dorsal areas of male Sprague-Dawley rats and subcutaneously injected with either morphine hydrochloride (5.0mg/kg) or indomethacin (2.5mg/kg) with a 27-gauge needle on day three post-wounding. On day five post-wounding, an injection of morphine hydrochloride, indomethacin or lambda-carrageenan (1.0%) into the granulation tissue was also administered. The withdrawal threshold of mechanical stimulation of the wound edge was compared in each group before treatment with injection and at two, four, eight and 24 hours after injection. Results: A total of 40 rats were used in the study. Since more severe inflammation in and around the wound was induced on day three post-wounding than that of day five, the withdrawal threshold measured on day three post-wounding was significantly lower than that of day five. The decrease of the withdrawal threshold was depressed by morphine hydrochloride and indomethacin treatment on day three post-wounding. While there was no significant difference between the changes in the withdrawal threshold after indomethacin treatment on day five post-wounding, we observed an increased withdrawal threshold after morphine hydrochloride treatment and decreased withdrawal threshold after lambda-carrageenan treatment on day five post-wounding. Conclusion: The results suggest that the von Frey test can be applied to measure the mechanical withdrawal threshold of full-thickness dorsal wounds in rats.

EFFICACY AND SAFETY OF MORPHINE HYDROCHLORIDE IN CANCER PATIENTS WITH CHRONIC PAIN

Purpose of the study: to assess the efficacy and safety of morphine hydrochloride in the form of 10 mg filmcoated tablets and 1 % solution for injection in cancer patients with chronic pain syndrome of strong intensity.Material and Methods. The study included 110 cancer patients with chronic pain syndrome of strong intensity. The study was conducted in compliance with the principles of the Helsinki Declaration, ICH GCP, GOST R 52379-2005, as well as other Russian laws regulating the conduct of clinical trials and work with opioid analgesics. Patients were randomized at a 1:1 ratio. Group I received 10 mg film-coated morphine tablets, 1 tablet orally every 4 hours for 7 days. Group II received 1 % morphine solution for injection, intramuscularly, 4 mg every 4 hours for 7 days. A Numeric Rating Scale for Pain (NRS, 0–100 mm) was used to assess the level of pain. The safety assessment was based on the collection of data on the registration of adverse events, including opioid-associated adverse effects.Results. Enteral and parenteral morphine administration for 7 days demonstrated a statistically significant decrease in the intensity of pain syndrome in cancer patients. The use of morphine hydrochloride in tablets reduced the number of additional analgesics prescribed for cancer patients. Regarding opioid-associated adverse effects, a statistically significant difference in the incidence of constipation between two groups was observed.Conclusion. The study showed that tablets and injectable dosage forms of morphine hydrochloride were comparable in efficacy and safety profile, thus predetermining the widespread clinical use of drugs produced by the domestic manufacturer in accordance with the “pain relief ladder”, proposed by WHO.

Improved Morphine-Loaded Hydrogels for Wound-Related Pain Relief

The use of morphine applied topically to painful wounds has potential advantages, such as dose reduction, fewer side effects and compound formulations, have been proposed for this purpose. Given the potential high impact of drug product quality on a patient’s health, the aim of the present study was to develop two stable sterile hydrogels containing morphine hydrochloride, intended for topical application on painful wounds. Two carboxymethylcellulose sodium-based hydrogels were prepared containing 0.125% w/w (F1-MH semi-solid formulation) and 1.0% w/w (F2-MH fluid formulation) morphine hydrochloride (MH), respectively. Studies included a risk assessment approach for definition of the quality target product profile (QTPP) and assessment of critical quality attributes (CQA) of the hydrogels to support product quality and safety. Safe, odourless, yellowish, translucent and homogeneous gels were obtained, with suitable microbiological and pharmaceutical characteristics. The active substance concentration was adapted according to the characteristics of the dose-metering device. Release profiles were investigated using Franz diffusion cells, and characterised by different kinetic models. Increasing gel viscosity prolonged drug release, with rates of 17.9 ± 2.2 μg·cm−2·h−1 (F1-MH) and 258.0 ± 30.4 μg·cm−2·h−1 (F2-MH), allowing for the reduction of the number of applications and improving patient compliance. The gels proved to be stable for up to 60 days at room temperature. The semi-solid and fluid MH-containing hydrogel formulations are safe, stable and suitable for use in hospital settings, which is rather important for wound-related pain management in cancer palliative care or burn patients.