Effect of antimycotics and rifampicin on the pharmacokinetics of buprenorphine and the feasibility of sublingual fentanyl for procedural sedation

Buprenorphine and fentanyl are opioids, which have been clinically used for decades. Buprenorphine is traditionally prescribed for maintenance therapy in opioid dependent patients and to a lesser extent in the treatment of acute pain. Fentanyl is the most widely used perioperative opioid. In recent years new dosage forms have been introduced for both of these drugs. The use of buprenorphine in the treatment of chronic pain has increased with the introduction of sublingual and transdermal formulations. Good results have been obtained with the administration of sublingual fentanyl in the treatment of cancer breakthrough pain. Some interaction studies have been made using high-dose buprenorphine and antiretrovirals, but there are few studies evaluating the drug-drug interactions between low-dose buprenorphine and known CYP3A4 inhibitors and inducers. In this thesis three studies were conducted to study the interactions between buprenorphine, using three different administration routes, and two CYP3A4 inhibitors, voriconazole and posaconazole and the CYP3A4 inducer, rifampicin. Voriconazole increased significantly the plasma concentration of sublingually and orally administered buprenorphine. Posaconazole also increased the plasma concentration of sublingually administered buprenorphine but the effect was not as evident as that encountered with voriconazole. Rifampicin decreased the plasma concentrations of sublingually administered buprenorphine, but it had no effect after the opioid’s intravenous administration. The aim of the fourth study was to evaluate the efficacy and safety of a sublingually administered fentanyl tablet in patients having colonoscopy. Patients often experience colonoscopy painful and unpleasant. Intravenous sedation increases the costs of colonoscopy significantly because patients need monitoring during sedation and recovery. The use of the sublingual administration route could offer a cost-effective alternative to intravenous sedation. This study showed that 100 micrograms of sublingual fentanyl was ineffective for the treatment of pain during colonoscopy. Nonetheless, it was observed that very few procedures had to be interrupted and the pain that patients experienced was mostly moderate. This raises the question of whether we should treat patients for anxiety and distress instead of pain

Management of Co-Occurring SUD and Chronic Pain

Though there has been a 44.4% decrease in the number of prescriptions written for opioid analgesics between the years 2011–2020 in the United States, drug overdose rates continue to climb sharply, reaching nearly 107,000 for a prior 12-months period as of early 2022, driven primarily by the use of illicit opioids. It is estimated that 80–90% of individuals with a substance use disorder (SUD) receive no treatment, and for those with opioid use disorder (OUD) who do find their way to treatment, less than half are offered potentially life-saving medication. Contemporaneously, chronic pain is one of the most common and most disabling health conditions, and frequently involves complex decision-making between the patient and the health care team regarding the treatment approach. Though prescribing trends have ebbed in recent years, opioids continue to be the most prescribed class of drug in the United States despite well-publicized associated harms. It is more critical than ever that stakeholders urgently work to facilitate and destigmatize evidence-based substance use disorder treatment, and promote safe, effective, and holistic care pathways for patients suffering from chronic pain

Formulation and Evaluation of Fast Disintegrating Sub Lingual Tablets of Rizatriptan

The active pharmaceutical ingredient Rizatriptan was subjected to preformulation studies, which encompasses the drug excipients compatibility study and the results obtained with selected excipients showed compatability with Rizatriptan drug. In the present study, fast disintegrating sublingual tablets of Rizatriptan 100mg were prepared by using croscamellose sodium, crospovidone and L-HPC as super disintegrants at the concentration of 3%, 4% and 5% of each and compared the effect of each at different concentrations, and finished the optimum formulation. A total number of 10 formulations were prepared by using different super disintegrants at different concentrations. Among this, formulation F-10 showed maximum effect but formulation F-3 was selected as best formulation because of its wonderful mouth feel which contains drug (5mg), crospovidone 5mg, mannitol (87mg), aspartame(2.5mg) and magnesium stearate(0.5mg). Stability studies were also done for the formulation F-3. Various physico-chemical parameters are tested for this formulation showed good results. From the release study and mathematical models it was concluded that the novel formulation can bypass the first pass metabolism and produced the quicker onset of action

Test-retest reliability of evoked heat stimulation bold functional magnetic resonance imaging

To date, the blood oxygenated-level dependent (BOLD) functional magnetic resonance imaging (fMRI) technique has enabled an objective and deeper understanding of pain processing mechanisms embedded within the human central nervous system (CNS). In order to further comprehend the benefits and limitations of BOLD fMRI in the context of pain as well as the corresponding subjective pain ratings, we evaluated the univariate response, test-retest reliability and confidence intervals (CIs) at the 95% level of both data types collected during evoked stimulation of 40°C (non-noxious), 44°C (mildly noxious) and a subject-specific temperature eliciting a 7/10 pain rating. The test-retest reliability between two scanning sessions was determined by calculating group-level interclass correlation coefficients and at the single-subject level. Across the three stimuli, we initially observed a graded response of increasing magnitude for both visual analogue scale (VAS) pain ratings and fMRI data. Test-retest reliability was observed to be highest for VAS pain ratings obtained during the 7/10 pain stimulation (intraclass correlation coefficient (ICC) = 0.938), while ICC values of pain fMRI data for a distribution of CNS structures ranged from 0.5 to 0.859 (p < 0.05). Importantly, the upper and lower CI bounds reported herein could be utilized in subsequent trials involving healthy volunteers to hypothesize the magnitude of effect required to overcome inherent variability of either VAS pain ratings or BOLD responses evoked during innocuous or noxious thermal stimulation

DISCOVERY OF NOVEL PHARMACOTHERAPEUTICS FOR SUBSTANCE USE DISORDERS

Substance use disorders are serious health concerns in the United States. Furthermore, the National Survey on Drug Use and Health reports a continuous increase in substance use disorders in the United States during the last 10 years. However, there are not many effective pharmacotherapeutics available for substance use disorders. The current dissertation is focused on research aimed at discovering pharmacotherapeutics for substance use disorders. First part of dissertation focused on discovering methamphetamine (METH) use disorder therapeutics targeting specific mechanism of METH action on dopaminergic neurons. The second part of dissertation focused on opioids and cocaine use disorder therapeutics targeting rewarding pathway commonly activated by opioids and cocaine. With respect to METH, it induces release of dopamine (DA) in neuronal terminals by interacting with the vesicular monoamine transporter-2 (VMAT2) and DA transporter (DAT). VMAT2 inhibitors have been found by our research group to decrease METH-evoked DA release, METH-induced hyperlocomotion, and METH self-administration in rats. However, these VMAT2 inhibitors lacked selectivity and tolerance developed to these pharmacologic effects after repeated administration, thereby limiting their potential as pharmacotherapeutics for METH use disorders. In the current study, analogs from a novel scaffold were found to selectively inhibit VMAT2 and were evaluated using neurochemical and behavioral pharmacological approaches. R- and S-3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine (GZ-11610 and GZ-11608, respectively) exhibited 94- to 3450-fold selectivity for VMAT2 over human-ether-a-go-go (hERG) channel, DAT, serotonin transporter, and nicotinic acetylcholine receptors. GZ-11608 competitively and concentration-dependently inhibited METH-evoked DA release via VMAT2. Also, GZ-11610 (56-300 mg/kg, oral) and GZ-11608 (300 mg/kg, oral; 10-30 mg/kg, s.c.) reduced METH-induced hyperlocomotor activity in METH-sensitized rats. Furthermore, GZ-11608 (1-30 mg/kg, s.c.) inhibited METH self-administration, cue- and METH-induced reinstatement in a dose-dependent manner, and 30 mg/kg (s.c.), 10 mg/kg (s.c.), and 17 mg/kg (s.c.) produced significant effect, respectively. Importantly, the GZ-11608-induced decrease in METH self-administration was not surmounted by increasing the amount of METH available. GZ-11608 did not substitute for METH and did not serve as a reinforcer in rats self-administering METH and drug naïve rats, respectively. Thus, these VMAT2 inhibitors incorporating a new scaffold are novel leads for new pharmacotherapeutics to treat METH use disorders. Substances with high abuse potential including opioids and cocaine elevate extracellular DA concentration in the nucleus accumbens, and this mechanism has long been considered to underly substance-induced reward. DA in the nucleus accumbens originates from DA neuron cell bodies located in the ventral tegmental area in the midbrain. Interestingly, M5 muscarinic acetylcholine receptors (mAChRs) are proteins that are highly expressed on ventral tegmental area DA neurons. Also, studies investigating M5 mAChRs knockout mice showed reduced responding for cocaine in cocaine self-administration and decreased time spent in cocaine-paired and morphine-paired place preference studies. Pharmacological inhibition of M5 mAChRs function via microinfusing mAChR antagonists exhibiting no selectivity among M1-M5 mAChRs subtypes into the ventral tegmental area where expression of M5 mAChRs are dominant, reduced morphine-induced hyperlocomotion and cocaine seeking behaviors in rats. These studies support therapeutic potential of M5 mAChRs selectivity antagonists in opioids and cocaine use disorders. Thus, in the current study, affinity of a series of pethidine and quinuclidinyl N-phenylcarbamate analogs for M5 mAChRs was evaluated using in vitro and ex vivo neuropharmacological assays. Among the pethidine analogs, compound 6a showed the highest binding affinity at M5 (Ki = 0.38 µM), but also high affinity at M1 and M3 mAChRs (0.67 and 0.37 µM, respectively). Among the quinuclidinyl N-phenylcarbamate analogs, compound 13c exhibited the highest affinity at M5 (Ki = 1.8 nM), but also high affinity at M1, M2, M3 and M4 mAChRs (Ki = 1.6, 13, 2.6, 2.2 nM, respectively). Also, 13c acted as an agonist of mAChRs on oxotremorine-induced DA release from rat striatal slices. In addition, compound 13b was found exhibiting the highest selectivity (17-fold) at M3 over M2 mAChRs, suggesting potential of 13b as a chronic obstructive pulmonary disease therapeutics. Taken together, these novel analogs serve as leads for further discovery of subtype-selective M5 mAChR antagonists that may have potential as therapeutics for substance use disorders, as well as for chronic obstructive pulmonary disease

Social trauma and the mu-opioid system in depression

The overarching thesis under investigation is that the endogenous opioid system plays a key role in depression subsequent to traumatic childhood social experiences. This is suggested by the fact that animal work indicates that mu-opioids robustly mediate separation-distress, and that early social stressors lead to long term dysregulation in key related circuitries and neuroanatomical structures

The opioid system in depression

Opioid receptors are widely distributed throughout the brain and play an essential role in modulating aspects of human mood, reward, and well-being. Accumulating evidence indicates the endogenous opioid system is dysregulated in depression and that pharmacological modulators of mu, delta, and kappa opioid receptors hold potential for the treatment of depression. Here we review animal and clinical data, highlighting evidence to support: dysregulation of the opioid system in depression, evidence for opioidergic modulation of behavioural processes and brain regions associated with depression, and evidence for opioidergic modulation in antidepressant responses. We evaluate clinical trials that have examined the safety and efficacy of opioidergic agents in depression and consider how the opioid system may be involved in the effects of other treatments, including ketamine, that are currently understood to exert antidepressant effects through non-opioidergic actions. Finally, we explore key neurochemical and molecular mechanisms underlying the potential therapeutic effects of opioid system engagement, that together provides a rationale for further investigation into this relevant target in the treatment of depression

The brain signature of paracetamol in healthy volunteers: a double-blind randomized trial

International audienceBackground: Paracetamol’s (APAP) mechanism of action suggests the implication of supraspinal structures but no neuroimaging study has been performed in humans.Methods and results: This randomized, double-blind, crossover, placebo-controlled trial in 17 healthy volunteers (NCT01562704) aimed to evaluate how APAP modulates pain-evoked functional magnetic resonance imaging signals. We used behavioral measures and functional magnetic resonance imaging to investigate the response to experimental thermal stimuli with APAP or placebo administration. Region-of-interest analysis revealed that activity in response to noxious stimulation diminished with APAP compared to placebo in prefrontal cortices, insula, thalami, anterior cingulate cortex, and periaqueductal gray matter.Conclusion: These findings suggest an inhibitory effect of APAP on spinothalamic tracts leading to a decreased activation of higher structures, and a top-down influence on descending inhibition. Further binding and connectivity studies are needed to evaluate how APAP modulates pain, especially in the context of repeated administration to patients with pain