Brian A. Baldo

Important insights and consensus remain lacking for risk prediction of opioid-induced respiratory depression (OIRD), reversal of respiratory depression (RD), the pathophysiology of OIRD, and which sites make the most significant contribution to its induction. The ventilatory response to inhaled carbon dioxide is the most sensitive biomarker of OIRD. To accurately predict respiratory depression (RD), a multivariant RD prospective trial using continuous capnography and oximetry examining five independent variables, age ≥60, sex, opioid naivety, sleep disorders, and chronic heart failure (PRODIGY trial), were undertaken. Intermittent oximetry alone substantially underestimates the incidence of RD. Naloxone, with an elimination half-life of ∼33 min (cf. morphine 2–3 h; fentanyl and congeners only 5–15 min), has limitations for the rescue of patients with severe OIRD. Buprenorphine is potentially valuable in patients being treated long term since its high µ-receptor (MOR) affinity makes it difficult for an opioid of lower affinity (e.g., fentanyl) to displace it from the receptor. In the last decade, synthetic opioids, for example, fentanyl, its potent analogs such as carfentanil, and the benzimidazole derivative nitazene “superagonists” have contributed to the exponential growth in opioid deaths due to RD. The MOR, encoded by gene Oprm1, is widely expressed in the central and peripheral nervous systems, including centers that modulate breathing. Opioids bind to the receptors, but consensus is lacking on which site(s) makes the most significant contribution to the induction of OIRD. Both the preBötzinger complex (preBötC), the inspiratory rhythm generator, and the Kölliker-Fuse nucleus (KFN), the respiratory modulator, contribute to RD, but receptor binding is not restricted to a single site. Breathing is composed of three phases, inspiration, postinspiration, and active expiration, each generated by distinct rhythm-generating networks: the preBötC, the postinspiratory complex (PiCo), and the lateral parafacial nucleus (pF_L), respectively. Somatostatin-expressing mouse cells involved in breathing regulation are not involved in opioid-induced RD.

The phenylethylamine, 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’), is the prototypical example of an entactogen. Its original placement in highly restrictive drug usage categories in the US and UK, led to an inevitable restriction on MDMA neuroscience research and treatment. The dominant pharmacological effects of MDMA are its properties of release and inhibition of reuptake of amine neurotransmitter transporters for dopamine, norepinephrine, and serotonin. MDMA is an agonist of a wide range of receptors; its mood-altering effects are mediated via 5-HT_2A receptors; this receptor may also mediate its effects on body temperature, analgesia, and anxiolytic properties. The mechanisms underlying MDMA’s entactogenic properties of sociability and interpersonal closeness are not known but release and involvement of oxytocin, a peptide thought by some to be involved in social bonding, has been suggested. Adverse effects of MDMA are mostly transient; acute multiorgan adverse effects occurring during raves or crowded dance gatherings include dehydration, hyperthermia, seizures, rhabdomyolysis, disseminated intravascular coagulation, and acute renal failure. Deaths following MDMA taken by itself are rare compared to fatalities following coadministration with other drugs. A recent FDA-approved phase 3 clinical trial of MDMA for post-traumatic stress disorder (PTSD) led to the conclusion that MDMA-assisted therapy represents a potential breakthrough treatment meriting expedited clinical evaluation. Despite the ongoing deliberations by the FDA and EMA for approval of MDMA treatment of PTSD, the Australian Therapeutic Goods Administration (TGA) recently announced that after an evaluation of the therapeutic value, benefits, and risks of MDMA, it will permit its prescribing for the treatment of PTSD. Further examples of regulatory relaxation toward MDMA-assisted psychotherapy are underway. These include the FDA’s recently approved clinical trial to assess MDMA’s efficacy in the treatment of “asociality” in patients with schizophrenia and an open trial of MDMA treatment for alcohol-use disorder which showed decreased alcohol consumption. There are also ongoing studies on the little understood startle response, anxiety associated with life-threatening illness, and social anxiety in autistic adults.

MRGPRX2, a novel G_aq‐coupled human mast cell receptor, mediates non‐immune adverse reactions without the involvement of antibody priming. Constitutively expressed by human skin mast cells, MRGPRX2 modulates cell degranulation producing pseudoallergies manifesting as itch, inflammation and pain. The term pseudoallergy is defined in relation to adverse drug reactions in general and immune/non‐immune‐mediated reactions in particular. A list of drugs with MRGPRX2 activity is presented, including a detailed examination of three important and widely used approved therapies: neuromuscular blockers, quinolones and opioids. For the clinician, the significance of MRGPRX2 is considered as an aid in distinguishing and ultimately identifying specific immune and non‐immune inflammatory reactions. Anaphylactoid/anaphylactic reactions, neurogenic inflammation and inflammatory diseases with a clear or strongly suspected association with MRGPRX2 activation are examined. Inflammatory diseases include chronic urticaria, rosacea, atopic dermatitis, allergic contact dermatitis, mastocytosis, allergic asthma, ulcerative colitis and rheumatoid arthritis. MRGPRX2‐ and allergic IgE/FcεRI‐mediated reactions may be clinically similar. Importantly, the usual testing procedures do not distinguish the two mechanisms. Currently, identification of MRGPRX2 activation and diagnosis of pseudoallergic reactions is generally viewed as a process of exclusion once other non‐immune and immune processes, particularly IgE/FcεRI‐mediated degranulation of mast cells, are ruled out. This does not take into account that MRGPRX2 signals via β‐arrestin, which can be utilized to detect MRGPRX2 activation by employing MRGPRX2 transfected cells to assess MRGPRX2 activation via two pathways, the G‐protein‐independent β‐arrestin pathway and the G‐protein‐dependent Ca²⁺ pathway. Testing procedures, interpretations for distinguishing mechanisms, patient diagnosis, agonist identification and drug safety evaluations are addressed.

The increasing use of opioids in pregnant women has led to an alarming rise in the number of cases of neonates with drug-induced withdrawal symptoms known as neonatal opioid withdrawal syndrome (NOWS). NOWS is a toxic heterogeneous condition with many neurologic, autonomic, and gastrointestinal symptoms including poor feeding, irritability, tachycardia, hypertension, respiratory defects, tremors, hyperthermia, and weight loss. Paradoxically, for the management of NOWS, low doses of morphine, methadone, or buprenorphine are administered. NOWS is a polygenic disorder supported by studies of genomic variation in opioid-related genes. Single-nucleotide polymorphisms (SNPs) in CYP2B6 are associated with variations in NOWS infant responses to methadone and SNPs in the OPRM1, ABCB1, and COMT genes are associated with need for treatment and length of hospital stay. Epigenetic gene changes showing higher methylation levels in infants and mothers have been associated with more pharmacologic treatment in the case of newborns, and for mothers, longer infant hospital stays. Respiratory disturbances associated with NOWS are not well characterized. Little is known about the effects of opioids on developing neonatal respiratory control and respiratory distress (RD), a potential problem for survival of the neonate. In a rat model to test the effect of maternal opioids on the developing respiratory network and neonatal breathing, maternal-derived methadone increased apneas and lessened RD in neonates at postnatal (P) days P0 and P1. From P3, breathing normalized with age suggesting reorganization of respiratory rhythm-generating circuits at a time when the preBötC becomes the dominant inspiratory rhythm generator. In medullary slices containing the preBötC, maternal opioid treatment plus exposure to exogenous opioids showed respiratory activity was maintained in younger but not older neonates. Thus, maternal opioids blunt centrally controlled respiratory frequency responses to exogenous opioids in an age-dependent manner. In the absence of maternal opioid treatment, exogenous opioids abolished burst frequencies at all ages. Prenatal opioid exposure in children stunts growth rate and development while studies of behavior and cognitive ability reveal poor performances. In adults, high rates of attention deficit disorder, hyperactivity, substance abuse, and poor performances in intelligence and memory tests have been reported.

The list of drugs patients may be exposed to during the perioperative and postoperative periods is potentially extensive. It includes induction agents, neuromuscular blocking drugs (NMBDs), opioids, antibiotics, sugammadex, colloids, local anesthetics, polypeptides, antifibrinolytic agents, heparin and related anticoagulants, blue dyes, chlorhexidine, and a range of other agents depending on several factors related to individual patients’ clinical condition and progress in the postoperative recovery period. To avoid poor or ultrarapid metabolizers to a particular drug (for example tramadol and codeine) or possible adverse drug reactions (ADRs), some drugs may need to be avoided during or after surgery. This will be the case for patients with a history of anaphylaxis or other adverse events/intolerances to a known drug. Other drugs may be ceased for a period before surgery, e.g., anticoagulants that increase the chance of bleeding; diuretics for patients with acute renal failure; antihypertensives relative to kidney injury after major vascular surgery; and serotonergic drugs that together with some opioids may rarely induce serotonin toxicity. Studies of germline variations shown by genotyping and phenotyping to identify a predisposition of genetic factors to ADRs offer an increasingly important approach to individualize drug therapy. Studies of associations of human leukocyte antigen (HLA) genes with some serious delayed immune-mediated reactions are ongoing and variations of drug-metabolizing cytochrome CYP450 enzymes, P-glycoprotein, and catechol-O-methyltransferase show promise for the assessment of ADRs and non-responses to drugs, particularly opioids and other analgesics. Surveys of ADRs from an increasing number of institutions often cover small numbers of patients, are retrospective in nature, fail to clearly identify culprit drugs, and do not adequately distinguish immune-mediated from non-immune-mediated anaphylactoid reactions. From the many surveys undertaken, the large list of agents identified during and after anesthesia and surgery are examined for their ADR involvement. Drugs are classified into those most often involved, (NMBD and antibiotics); drugs that are becoming more frequently implicated, namely antibiotics (particularly teicoplanin), and blue dyes; those becoming less frequently involved; and drugs more rarely involved in perioperative, and postoperative adverse reactions but still important and necessary to keep in mind for the occasional potential sensitive patient. Clinicians should be aware of the similarities between drug-induced true allergic type I IgE/FcεRI- and pseudoallergic MRGPRX2-mediated ADRs, the clinical features of each, and their distinguishing characteristics. Procedures for identifying MRGPRX2 agonists and diagnosing and distinguishing pseudoallergic from allergic reaction mechanisms are discussed. Graphical Abstract

Insights into the pathophysiology of many non-immune-mediated drug reactions referred to as toxicities, sensitivities, intolerances, or pseudoallergies have resulted from research identifying the mastocyte-related G-protein-coupled receptor (GPCR) member X2 (MRGPRX2), a human mast cell receptor mediating adverse reactions without the involvement of antibody priming. Opioid-induced degranulation of mast cells, particularly morphine, provoking release of histamine and other preformed mediators and causing hemodynamic and cutaneous changes seen as flushing, headache and wheal and flare reactions in the skin, is an example of results of MRGPRX2 activation. Opioids including morphine, codeine, dextromethorphan and metazocine as well as endogenous prodynorphin opioid peptides activate MRGPRX2 at concentrations causing mast cell degranulation. Unlike the canonical opioid receptors, MRGPRX2 shows stereochemical recognition preference for dextro rather than levo opioid enantiomers. Opioid analgesic drugs (OADs) display a range of histamine-releasing potencies from the strong releaser morphine to doubtful releasers like hydromorphone and the non-releaser fentanyl. Whether there is a correlation between histamine release by individual OADs, MRGPRX2 activation, and presence or absence of adverse cutaneous effects is not known. To investigate the question, ongoing research with recently pursued methodologies and strategies employing basophil and mast cell tests resulting from MRGPRX2 insights should help to elucidate whether or not an opioid's histamine-releasing potency, and its property of provoking an adverse reaction, are each a reflection of its activation of MRGPRX2.

Opioid-induced respiratory depression (OIRD), the primary cause of opioid-induced death, is the neural depression of respiratory drive which, together with a decreased level of consciousness and obstructive sleep apnea, cause ventilatory insufficiency. Variability of responses to opioids and individual differences in physiological and neurological states (e.g., anesthesia, sleep-disordered breathing, concurrent drug administration) add to the risk. Multiple sites can independently exert a depressive effect on breathing, making it unclear which sites are necessary for the induction of OIRD. The generator of inspiratory rhythm is the preBötzinger complex (preBötC) in the ventrolateral medulla. Other important brainstem respiratory centres include the pontine Kölliker-Fuse and adjacent parabrachial nuclei (KF/PBN) in the dorsal lateral pons, and the dorsal respiratory group in the medulla. Deletion of μ opioid receptors from neurons showed that the preBötC and KF/PBN contribute to OIRD with the KF as a respiratory modulator and the preBötC as inspiratory rhythm generator. Glutamatergic neurons expressing NK-1R and somatostatin involved in the autonomic function of breathing, and modulatory signal pathways involving GIRK and KCNQ potassium channels, remain poorly understood. Reversal of OIRD has relied heavily on naloxone which also reverses analgesia but mismatches between the half-lives of naloxone and opioids can make it difficult to clinically safely avoid OIRD. Maternal opioid use, which is rising, increases apneas and destabilizes neonatal breathing but opioid effects on maternal and neonatal respiratory circuits in neonatal abstinence syndrome (NAS) are not well understood. Methadone, administered to alleviate symptoms of NAS in humans, desensitizes rats to RD.