Dynamic Computational Models and Simulations of the Opioid Crisis: A Comprehensive Survey

Opioids have been shown to temporarily reduce the severity of pain when prescribed for medical purposes. However, opioid analgesics can also lead to severe adverse physical and psychological effects or even death through misuse, abuse, short- or long-term addiction, and one-time or recurrent overdose. Dynamic computational models and simulations can offer great potential to interpret the complex interaction of the drivers of the opioid crisis and assess intervention strategies. This study surveys existing studies of dynamic computational models and simulations addressing the opioid crisis and provides an overview of the state-of-the-art of dynamic computational models and simulations of the opioid crisis. This review gives a detailed analysis of existing modeling techniques, model conceptualization and formulation, and the policy interventions they suggest. It also explores the data sources they used and the study population they represented. Based on this analysis, direction and opportunities for future dynamic computational models for addressing the opioid crisis are suggested.

Shifting interpretations in evidence and guidance in pain and opioids research: A bibliometric analysis of a highly cited case series from 1986

Rationale, aims, and objectives: Portenoy and Foley’s 1986 landmark study “Chronic use of opioid analgesics in non-malignant pain: report of 38 cases” has been reproached for opening the floodgates of opioid prescribing for chronic non-cancer pain and the attendant harms. This influential article has been cited over 500 times in the scientific literature over the last four decades. This study seeks to understand the impact of Portenoy and Foley’s article on subsequent discussions and research about opioids. Methods: We conducted a multi-method bibliometric analysis of all citations of this article from 1986 through 2019 using quantitative relational and qualitative content analysis to determine how uses and interpretations of this case series and associated prescribing guidance have changed over time, in relationship to the evolution of the North American opioid crises. Results: Using time series analysis, we identified three periods with distinct interpretations and uses of the index study. In the first “exploration” period (1986-1996), the index study was well-received by the scientific community and motivated further study of the effects of opioids. In the second “implementation” period (1997-2003, coinciding with the release of OxyContin®), this study was used as evidence to support widespread prescribing of opioid analgesics, even while it was recognized that long-term effects had not yet been evaluated. The third “reassessment” period (2004-2019) focused on how opioid-related harms had been overlooked, and in many cases these harms were directly attributed to this study. Conclusion: These changes in interpretation demonstrate shifting currents of the use and mobilization of evidence regarding pain and opioids, and how these currents both impact and are impacted by clinical practices and major sociohistorical phenomena such as the opioid crisis. Researchers and clinicians must account for these shifting dynamics when developing and interpreting scientific knowledge, including in the form of clinical practice guidelines.

Cannabinoids in Chronic Pain: Therapeutic Potential Through Microglia Modulation

Chronic pain is a complex sensory, cognitive, and emotional experience that imposes a great personal, psychological, and socioeconomic burden on patients. An estimated 1.5 billion people worldwide are afflicted with chronic pain, which is often difficult to treat and may be resistant to the potent pain-relieving effects of opioid analgesics. Attention has therefore focused on advancing new pain therapies directed at the cannabinoid system because of its key role in pain modulation. Endocannabinoids and exogenous cannabinoids exert their actions primarily through Gi/o-protein coupled cannabinoid CB1 and CB2 receptors expressed throughout the nervous system. CB1 receptors are found at key nodes along the pain pathway and their activity gates both the sensory and affective components of pain. CB2 receptors are typically expressed at low levels on microglia, astrocytes, and peripheral immune cells. In chronic pain states, there is a marked increase in CB2 expression which modulates the activity of these central and peripheral immune cells with important consequences for the surrounding pain circuitry. Growing evidence indicate that interventions targeting CB1 or CB2 receptors improve pain outcomes in a variety of preclinical pain models. In this mini-review, we will highlight recent advances in understanding how cannabinoids modulate microglia function and its implications for cannabinoid-mediated analgesia, focusing on microglia-neuron interactions within the spinal nociceptive circuitry.

Neck pain: diagnostic and therapeutic features

Neck pain is a fairly common complaint when visiting a doctor, its occurrence frequency is 10–21% per year, and neck pain takes the 4th place among the causes of disability; almost 50% of patients continue to experience unpleasant sensations or repeated pain episodes. The elderly people are the most prone to the neck pain, this is associated with the progressive degenerative changes in the facet joints and intervertebral discs. However, reasons of this symptom can be of different kinds. Cervicalgia diagnosis is directed primarily to eliminate symptomatic pains associated with severe somatic pathology, immune diseases, infections and oncology. Comorbid diseases and risk factors can combine with each other causing the polyetiologic pain syndrome. Main steps of the cervicalgia diagnostic algorithm are the following: collection of complaints and anamnesis in detail, physical and neurological examination, and also use of visualization methods. Visualization and electrodiagnostic methods are not always informative for patients with chronic cervicalgia and in the degenerative etiology of the syndrome. MRI and the surgeon consultation must be recommended to patients with deteriorating neurological symptoms or with long-term constant pain. Conservative therapy of cervicalgia implies a combination of non-drug methods (compliance with regime, orthopedic treatment, leaf, physiotherapy, etc.) and pharmacotherapy. The last depends on the presence of a neuropathic component of pain and the duration of pain syndrome. The pain therapy with a nociceptive nature is usually implies a combination of non-steroidal anti-inflammatory remedies, non-opioid analgesics and muscle relaxants. Whereas neuropathic pains first-line preparations are tricyclic antidepressants, duloxetine, venlafaxine, pregabalin, gabapentine. The therapy success depends on the proper individual estimation of the pain factors, pain chronization and possible treatment complications. The therapeutic forecast of the acute nonspecific cervicalgia is usually good, but it becomes less predictable if the pain acquires chronic character.

Hypothesizing in the Face of the Opioid Crisis Coupling Genetic Addiction Risk Severity (GARS) Testing with Electrotherapeutic Nonopioid Modalities Such as H-Wave Could Attenuate Both Pain and Hedonic Addictive Behaviors

In the United States, amid the opioid overdose epidemic, nonaddicting/nonpharmacological proven strategies are available to treat pain and manage chronic pain effectively without opioids. Evidence supporting the long-term use of opioids for pain is lacking, as is the will to alter the drug-embracing culture in American chronic pain management. Some pain clinicians seem to prefer classical analgesic agents that promote unwanted tolerance to analgesics and subsequent biological induction of the “addictive brain”. Reward genes play a vital part in modulation of nociception and adaptations in the dopaminergic circuitry. They may affect various sensory and affective components of the chronic pain syndromes. The Genetic Addiction Risk Severity (GARS) test coupled with the H-Wave at entry in pain clinics could attenuate pain and help prevent addiction. The GARS test results identify high-risk for both drug and alcohol, and H-Wave can be initiated to treat pain instead of opioids. The utilization of H-Wave to aid in pain reduction and mitigation of hedonic addictive behaviors is recommended, notwithstanding required randomized control studies. This frontline approach would reduce the possibility of long-term neurobiological deficits and fatalities associated with potent opioid analgesics.

Costs and consumption of analgesics, with special reference to opiates in Serbia and Montenegro from 2015 to 2019

Background/Aim: Patients in developing countries do not always receive adequate painrelieving treatment. Monitoring of analgesic consumption is of great importance, since this can help assessing the quality of painful condition management. The aim of this paper is to present a five-year consumption and costs of drugs with analgesic effects in developing countries, exemplified by Serbia and Montenegro, and indicate the main reasons for their (in)adequate prescribing. Methods: The observational, retrospective, cross-sectional study was conducted in order to analyse consumption of all analgesics, both opioid and non-opioid, in Serbia and Montenegro, as developing countries. The data concerning analgesic consumption and drug prices were obtained from annual editions of the publications of the Medicines and Medical Devices Agency of Serbia and Montenegro. The WHO methodology with defined daily dose (DDD) as a unit of measure (it is defined by the number of DDD per 1000 inhabitants per day) was used in these publications. Results: In the course of the fiveyear period (from 2015 to 2019) in Serbia, the total allocations for analgesic therapy had a rising trend; from about 43.6 million to 63.3 million of Euros, while in Montenegro expenditures showed annual variations with highest value in 2018. Most of the money in both countries was invested in M01A group of drugs, for which the highest consumption was also recorded. Significantly higher consumption of opioid analgesics in Montenegro comparing with Serbia was observed in the same period, and it predominatly reflected the difference in fentanyl (N02AB03, transdermal patch) prescribing. In Montenegro, consumption of M01group of drugs was prominently higher in comparison to M01AE group during the whole five-year period, similarly like in Serbia in which this was not the case only in 2018. Conclusions: Taking into account the importance of analgesics for everyday medical practice, more rational prescribing of these drugs is necessary both in Serbia and Montenegro in the future.

Opioid Epidemic: Diagnosed, Started on Treatment?

In the March 2021 issue of the journal Pharmacoepidemiology Drug Safety, an article by K. Bykov et al. was published, which contains an analysis of the use of opioid and non-opioid analgesics in US clinics in the period 20072017. According to the authors, the frequency of use of drugs in this group does not tend to decrease, despite the previously announced opioid epidemic in the USA. In Russia, the problem of the emergence of opioid dependence due to the perioperative use of drugs of this group is of little relevance. The existing legal restrictions on the prescription of opioid analgesics minimize this risk. But these same limitations make the idea of opioid-free analgesia very attractive in our country.