Effectiveness of the methadone programme in the treatment of patients on a mephedrone binge and dependent on heroin: a retrospective study, 2010-19.

Objectives: The purpose of this research was to investigate the effectiveness of the methadone programme in a group of patients taking mephedrone with heroin.Methods: The research involved 230 people who took part in the methadone programme between 2010 and 2019: 101 people on a mephedrone binge and taking heroin and 129 people addicted to heroin.Results: Number of re-hospitalisations was higher in a group of patients on a mephedrone binge taking heroin in comparison to heroin dependent patients (91.9 vs 79.8%, p < 0.01). The interaction of the hepatitis C virus (HCV) infection with the dose of methadone taken explains 67.6% of the variance in the frequency of hospitalisation of the patients on a mephedrone binge (p < 0.001), and in the case of the dose of methadone alone - only 12% (p < 0.001). Regression analysis indicated that statistically significant majority of the subjects (p < 0.001) who received the optimal dose of methadone, namely 100-110 ml, were hospitalised once.Conclusions: The interaction of the methadone dose with HCV infection plays a very important role in the frequency of hospitalisation of patients taking mephedrone with heroin on a regular basis.KEY POINTSThe number of hospitalisations was higher in a group of patients on a mephedrone binge taking heroin in comparison to heroin dependent patientsThe interaction of the sex of the subjects and HCV infection with the dose of methadone taken explains 80.3 and 67.6% of variance in the frequency of hospitalisations, respectivelyThe most optimal dose of methadone in the group of people taking mephedrone with heroin ranges between 100 and 110 ml.

Biological evaluation and molecular docking studies of AA3052, a compound containing a µ-selective opioid peptide agonist DALDA and d-Phe-Phe-d-Phe-Leu-Leu-NH2, a substance P analogue.

The design of novel drugs for pain relief with improved analgesic properties and diminished side effect induction profile still remains a challenging pursuit. Tolerance is one of the most burdensome phenomena that may hamper ongoing opioid therapy, especially in chronic pain patients. Therefore, a promising strategy of hybridizing two pharmacophores that target distinct binding sites involved in pain modulation and transmission was established. Previous studies have led to the development of opioid agonist/NK1 agonist hybrids that produce sufficient analgesia and also suppress opioid-induced tolerance development. In our present investigation we assessed the antinociceptive potency of a new AA3052 chimera comprised of a potent MOR selective dermorphin derivative (DALDA) and an NK1 agonist, a stabilized substance P analogue. We have shown that AA3052 significantly prolonged responses to both mechanical and noxious thermal stimuli in rats after intracerebroventricular administration. Additionally, AA3052 did not trigger the development of tolerance in a 6-day daily injection paradigm nor did it produce any sedative effects, as assessed in the rotarod performance test. However, the antinociceptive effect of AA3052 was independent of opioid receptor stimulation by the DALDA pharmacophore as shown in the agonist-stimulated G-protein assay. Altogether the current results confirm the antinociceptive effectiveness of a novel opioid/SP hybrid agonist, AA3052, and more importantly its ability to inhibit the development of tolerance.

Antinociceptive effect induced by a combination of opioid and neurotensin moieties vs. their hybrid peptide [Ile(9)]PK20 in an acute pain treatment in rodents.

Hybrid compounds are suggested to be a more effective remedy for treatment of various diseases than combination therapy, since the attenuation or total disappearance of side effects, typically induced by a single moiety, can be observed. This is of great importance, especially when we consider problems resulting from the use of opioid analgesics. However, although it seems that such compounds can be valuable therapeutic tools, the lack of conviction among the public as to the appropriateness of their use still remains; therefore patients are commonly treated with polypharmacy. Thus, in the presented paper we show a comparison of the antinociceptive effect between a novel opioid-neurotensin chimera called [Ile(9)]PK20 and a mixture of its structural elements, delivered intrathecally and systemically. Additionally, motor coordination was assessed in the rotarod test. The results clearly indicate that spinal administration of the examined compounds, resulted in a long-lasting, dose- and time-dependent antinociceptive effect. Although the mixture of both pharmacophores was found to be more active than [Ile(9)]PK20, motor impairments surfaced as a side effect. This in turn illustrates the advantageous use of hybrid structures over drug cocktails.

Influence of nitric oxide synthase or cyclooxygenase inhibitors on cannabinoids activity in streptozotocin-induced neuropathy.

BACKGROUND: Influence of a relatively specific inhibitor cyclooxygenase (COX)-2, celecoxib, a relatively specific inhibitor of neuronal nitric oxide synthase (NOS), 7-Ni, and a relatively selective inhibitor of inducible NOS, L-NIL, on the action of a preferentially selective CB1 cannabinoid receptor agonist, Met-F-AEA and a selective CB2 cannabinoid receptor agonist, AM 1241 was investigated, in a streptozotocin (STZ)-induced neuropathy. METHODS: Studies were performed on male Wistar rats. Changes in nociceptive thresholds were determined using mechanical stimuli - the modification of the classic paw withdrawal test described by Randall-Selitto. Diabetes was induced by a single administration of STZ. RESULTS: In a diabetic neuropathic pain model, pretreatment with celecoxib, L-NIL and 7-Ni, significantly increased the antihyperalgesic activity of both Met-F-AEA and AM 1241. CONCLUSIONS: The results of this study seemed to indicate that the interaction between cannabinoid, COX-2 and NOS(s) systems might exist. Concomitant administration of small doses of CB1 and/or CB2 receptor agonists and COX-2 or NOS inhibitors can be effective in the alleviation of diabetic neuropathic pain.