Opioids: Practice and Pharmacology

The “Opioid Crisis” is a term referring to the current misuse of opioids causing epidemic-sized proportions of mortality and economic burden. The Substance Abuse and Mental Health Services Administration (SAMHSA) reported a survey conducted in 2017 showing 11.1 million people, age 12 and older, as having misused prescription pain relievers in the past year; 953,000 of 1.7 million with pain reliever use disorder claimed to be receiving treatment, while 47,872 deaths were associated with opioid use (USHHS 2018). The exponential increase in opioid misuse and related deaths over the past two decades are the consequence of several consonant factors involving medical practitioners’ views on undertreating pain, which has recently been deemed the ‘fifth’ vital sign by the Joint Commission at the behest of the American Pain Society and obtained status among fundamental human rights via the Declaration of Montreal, pharmaceutical corporation production and marketing campaigns, as well as black market diversions and hazardous mixtures (USHHS 2018, Vadivelu et al 2018). Encouraged by pharmaceutical companies, most notoriously Purdue Pharma, medical practitioners prescribed opioid pain-relievers to patients, some with high-risk of abuse such as military veterans and adolescent athletes, without the proper education or treatment observation that either led to an increased availability of unused prescription opiates for diversion or generated abuse disorders substantiated by illicitly manufactured opiates (Vadivelu et al 2018)⁴⁵. Opioid-related side effects can result in prolonged hospitalizations, adding to the economic burden straining the healthcare system, as well as eliciting Neonatal Abstinence Syndrome (NAS), a condition of withdrawal symptoms exhibited by newborns who have adapted to opiates ingested by the mother during pregnancy (USHHS 2018, Vadivelu et al 2018). In an effort to reverse the epidemic, government initiatives have held pharmaceutical companies accountable for misleading clients in the form of lawsuits and increased regulation, pain medication protocols for prescribers have been developed, funding for treatment centers has been issued, and scientific research has investigated alternatives to opiates for pain relief (Murthy 2016, Vadivelu et al. 2018, Everson et al. 2020). Acute and chronic pain are synonymous with most medical conditions and clinical procedures, yet, as the medical community acknowledges the risks of opioid analgesics, attention is directed towards enhanced recovery after surgery (ERAS) protocols, which are systematic approaches to perioperative care that tailors pharmacologic and non-pharmacologic interventions, and multimodal pharmaceutical regimens that incorporate non-steroidal anti-inflammatory drugs (NSAIDs; i.e. celecoxib, ketorolac, or acetaminophen), anesthetics (i.e. ketamine), anticonvulsants (i.e. gabapentin), glucocorticoids, or alpha-adrenergic agonists in low-opioid or opioid-free combinations to ween the patient from dependence while maintaining optimal analgesic effect (Everson et al 2020).

Generally, opiates comprise a class of drugs structurally similar to alkaloids originally extracted from the seed capsules of Papaver somniferum, including phenanthrenes morphine and codeine, but have extended to morphine-like compounds morphinans and benzomorphans, in addition to structurally distinct methadones, phenylpiperidines, and propionanilides that demonstrate similar pharmacological profiles (Goodman et al. 2013). Opiates demonstrate specificity for at least one of the µ-, δ-, or κ-opioid receptors, which are G_i/o-GPCRs expressed on neurons of the CNS and PNS, but also in the neuroendocrine and immune systems, and possess endogenous ligands that are peptide derivatives of prepro-opiomelanocortin (POMC), proenkephalin, and prodynorphin, encoding endorphins, enkephalins, and dynorphins, respectively (Goodman et al. 2013, Stein 2015). At their N-terminals, endogenous opioids contain a conserved sequence of five peptides known as the ‘opioid motif’ consisting of Tyrosine-Glycine-Glycine-Phenylalanine-Methionine/Leucine, whereby the hydrophobic side-chain of the phenylalanine functions as an ‘address’ component separated by a two glycine ‘linker’ connecting the ‘message’ component with positively charged amine; in fact the ligand ‘address-linker-message’ motif informed the Beckett and Casy model of the orthosteric site, that current biophysical studies have confirmed, by the presence of an anionic residue aligned with accommodating cavity and flat hydrophobic surface that has guided synthetic opiate drug development (Goodman et al. 2013, Manglik 2020). Indeed, specific ligand induced receptor conformation, whose activation is proposed to involve a ̴10Å outward displacement of transmembrane helix 6 (TM6), is of intense interest as µ- and δ-opioid GPCRs are rapidly endocytosed via β-arrestin recruitment causing desensitization, which is related to the development of tolerance and may potentially be avoided with effective bias-agonists (Goodman et al. 2013, Manglik 2020).

Figure 6: A) Diagram of Efferent Neurons involved with Pain Perception and Nuclei Effect by Opioid Induced Anti-nociception and Addiction. B) Diagram of GABAergic Neuron as a Target of Opioid Induced 'Disinhibition'. AM=Amygdala, RMTg=Rostral Medial Tegmentum, VP=Ventral Pallidus, PAG=Periaqueductal Grey, RVM=Rostro Ventromedial Medulla, DRG=Dorsal Root Ganglion, D1/D1=Dopamine Receptor 1/2, MOR=µ-opioid receptor, AC=Adenylyl Cyclase, GIRK=G-protein coupled potassium inward rectifier channel , DA=Dopamine, GABA=γ-aminobutyric acid, Glut= Glutamate, NE=norepinephrine, cAMP=cyclic AMP.

Abuse liability of many pharmaceuticals has been correlated to the modulation in activity of the mesolimbic system of the CNS and the primary involvement of the dopaminergic projections of the ventral tegmental area (VTA) to the nucleus accumbens (NAc), medial prefrontal cortex (mPFC), amygdala (AM), and anterior cingulate cortex (ACC) as a determinant of thalamocortical control in executive decision making, emotional perception, and motivational drive (Cooper et al. 2017, Serafini et al. 2020). The Office of the Surgeon General and SAMHSA depict the cognitive cycle of addiction as involving the basal ganglia, extended amygdala, and prefrontal cortex as sequentially operational in binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation behaviors, respectively (USHHS 2018). The antinociceptive properties of opioids is related to their effect on the descending pain pathway in response to signals received by the ascending spinothalamic and spinoreticulothalamic tract, which is initiated by high-threshold Aδ (myelinated; types I and II) and C (unmyelinated) fibers, as well as low-threshold Aβ afferent fibers, that integrate with dorsal root ganglion connecting ascending neurons within laminae of the spinal dorsal horn (Basbaum et al. 2009; see Figure 6A). Subcortical regions, the periaqueductal gray (PAG) and rostral ventromedial medulla (RVM), integrate cortical inputs in response to pain and direct anti- and pronociceptive neurotransmission along descending laminae of the spinal dorsal horn (Basbaum et al. 2009, Ossipov et al. 2014, Lau & Vaughan 2014). Pharmaceutical opiates for pain-relief (i.e. morphine, fentanyl) primarily show selective agonism for µ-opioid receptors (MOR) and are able to exert pre- and post-synaptic inhibition of MOR on GABAergic interneurons of the PAG to offer a ‘disinhibitory’ action on excitatory glutamatergic projection to the RVM, which stimulates the release of serotonin and norepinephrine to mitigate neurotransmission of the ascending pathway (Basbaum et al. 2009, Lau & Vaughan 2014, Lupetow et al. 2018, Oliva & Wanat 2016; see Figure 6B). Similarly, opiates disinhibit dopamine release in the mesolimbic pathway via inhibiting GABAergic projections to the VTA from the NAc and rostro medial tegmentum (RMTg; Goodman et al 2013, Corre et al. 2018, Lau & Vaughan 2014, Lupetow et al. 2018). Chronic opioid exposure is suggested to elicit an allostatic load capable of redefining homeostatic set points that manifests in symptoms of hyperalgesia and hyperkatefia, or hypersensitivity to emotional distress (Shurman et al. 2010). The development of tolerance to opiates results in altered signaling cascades of MORs from inhibitory to stimulatory effectors (i.e. increasing GABA release from GABAergic neurons), while desensitization is loss of receptor due to βarrestin mediated endocytosis, both of which contribute to allostatic load (Lupetow et al. 2018). Additionally, studies show glial cells contribute to tolerance as opioid activation of Toll-like receptor 4 (TLR4) induces the release of TNFα and IL-1β from microglia to upregulate post-synaptic AMPA and NMDA receptors, downregulate post-synaptic GABA receptors, as well as downregulate glutamate transporters while inducing the release of glutamate from neighboring astrocytes to potentiate pre-synaptic neurotransmission (Zhang et al. 2020, Lupetow et al. 2018). Brain-derived neurotrophic factor (BDNF), another microglial cytokine upregulated by opioids, has also been found to operate an ancillary enhancement of increased dopamine in the NAc as BDNF downregulates expression of potassium chloride cotransporter 2 (KCC2) on VTA GABAergic neurons, thus reducing the membrane potential such that GABA signaling to the VTA becomes excitatory (Zhang et al. 2020). In sum, the pathophysiology of opioid abuse disorder is of interest to on-going research with the aims of developing safer pharmaceuticals.