Pharmacokinetic and pharmacodynamic considerations in developing a response to the opioid epidemic

Abstract

Introduction:

Opioids continue to be used widely for pain management. Widespread availability of prescription opioids has led to opioid abuse and addiction. Besides steps to reduce inappropriate prescribing, exploiting opioid pharmacology to make their use safer is important.

Areas covered:

This article discusses the pathology and factors underlying opioid abuse. Pharmacokinetic and pharmacodynamic properties affecting abuse liability of commonly abused opioids have been highlighted. These properties inform development of ideal abuse deterrent products. Mechanisms and cost-effectiveness of available abuse deterrent products have been reviewed in addition to the pharmacology of medications used to treat addiction.

Expert opinion:

The opioid crisis presents unique challenges to managing pain effectively given the limited repertoire of strong analgesics. The 5-point strategy to combat the opioid crisis calls for better preventive, treatment and recovery services, better data, better pain management, better availability of overdose-reversing drugs and better research. There is an urgent need to decrease the cost of abuse deterrent opioids which deters their cost-effectiveness. In addition, discovery of novel analgesics, further insight into central and peripheral pain mechanisms, understanding genomic risk profiles for efficient targeted efforts, and education will be key to winning this fight against the opioid crisis.

1. Introduction and definitions

The opioid epidemic has been declared a public health emergency in the United States (US). As per the statistics provided by U.S. Department of Health & Human Services (HHS), there are more than 130 deaths every day from opioid overdose, and almost 400,000 people have died from (any) opioid overdose between 1999 to 2017 [1, 2]. The three waves of opioid overdose deaths are related to misuse of prescription opioids, heroin and illicitly manufactured fentanyl [3, 4]. In 2018, 10.3 million people misused opioids of whom 9.4 million misused the pain reliever prescription and 0.8 million used heroin. Around 2.0 million misused prescription opioids for the first time and 2.0 million had an opioid use disorder [1]. The promising downward “trend” (5% decrease) in the rate of overdose deaths between 2017 and 2018 may warrant some cautious optimism though it remains to be seen whether the trend continues.

Opioid abuse can be described as “any intentional use of opioids outside of a physician’s prescription for a bona fide medical condition, excluding accidental misuse” [5]. Accidental misuse refers to unintentional overdose of prescription opioid due to confusion or mix up with other drugs. Addiction or dependence has been defined by American Psychiatric Association as “compulsive use, impaired control, tolerance, withdrawal and continued use despite physical and psychological problems caused or exacerbated by use” [6]. Apart from opioid induced toxicity, addiction affects individual wellbeing in various ways. There is higher probability of transfer of blood borne pathogens among opioid abusers leading to HIV, hepatitis C virus infection, and bacterial infection. Similarly, opioid abuse is associated with occurrence of many other social problems such as perpetuating crime, increased death rate, legal problems and higher unemployment rate [7].

Ironically 60% of opioid prescriptions are legitimately obtained from medical practitioners, while others get them from friends/relatives, drug dealers or by doctor shopping [8]. Due to these factors, initiatives such as monitoring the prescription of pain killers by health authorities are only partially effective [8]. The five-point HHS strategy unveiled in 2017 prioritizes improved access to prevention, treatment, and recovery support services. Accordingly, a substantial increase in substance abuse facilities has been seen, and about 1.27 million Americans are now receiving medication assisted treatment (MAT) for substance abuse. Considering the magnitude of the opioid crisis, it is imperative to understand the various facets of this problem. That will help in planning more effective and practical strategies to control it. In the current review, we briefly discuss pathogenic factors predisposing individuals (psychological and genetic) to abuse, following which we summarize the pharmacokinetics (PK) and pharmacodynamic (PD) properties of opioids which contribute to higher abuse potential, how principles of opioid PK-PD could be employed to devise better opioid abuse deterrent formulations (ADF), current and novel opioid abuse deterrents and relevant pharmacology pertaining to MAT.

2. Pathogenesis of opioid abuse disorder

Whichever may be the route of uptake, opioids ultimately enter blood circulation and reach the brain. After crossing blood-brain-barrier, opioids enter the brain cells and produce effect by binding to opioid receptors located in brain. The opioid-receptor complex activates the mesolimbic reward system in ventral tegmental area, resulting in release of the neurotransmitter dopamine in nucleus accumbens area of brain. Depending on the intense feeling of pleasure or reward perceived upon administration of opioid, an individual may be more inclined to repeated administration and of addiction [9].

Addictive drugs primarily act on neural circuits that activate motivated adaptive behaviors, [10] among which the mesolimbic dopamine system, endogenous opioidergic system and the gamma-aminobutyric acid (GABA)-ergic systems play major roles. The interplay of these systems has been shown to be that activation of mu-opioid receptors inhibit GABA-ergic inter-neurons, which allows dopaminergic neurons to release more dopamine into the reward pathway, creating a positive reinforcement of pleasurable feelings [11]. Neuroimaging studies have also shown that the prefrontal cortex which regulates the limbic reward regions and is involved in decision-making (self-control, salience attribution and awareness) also plays an important role in determining loss of control over drug intake [12]. In animal models, long term use of opioids has been found to have a broad range of effects on the amygdala, including decreased mu-opioid receptor sensitivity, and modulated glutamate and gamma amino butyric acid functioning [13–15]. These changes were further shown to alter brain functional connectivity and decreased brain volume with an impact on learning and memory, thus further impairing brain function and control [16, 17]. An abuser feels the urge to continue taking opioids to avoid the withdrawal symptoms (opioid dependence) or experience craving to feel high (opioid addiction) [9].

3. Factors behind opioid crisis

3.1. Motivation behind substance abuse

Understanding the motivation behind opioid abuse and factors contributing to it is important for development of successful preventive and therapeutic strategies. Most of this information is qualitative and arise from studies using focus groups and structured interviews. A systematic review aiming to analyze qualitative studies on the progression from initial use to abuse, included 17 studies conducted over 20 years (1996–2016) [18]. The studies investigated factors leading to substance abuse in opioid abusers in a variety of settings. The most significant factors reported were increased availability of opioids fueled by the recommendations for “pain to be the fifth vital sign” endorsed by the Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) [19] and the introduction of sustained release oxycodone which was touted to have lower abuse potential due to slow release not eliciting an immediate reward state. The false “safety net” afforded by legally obtained prescription drugs and more reliable “highs” compared to substances like heroin, were also factors that often were used in justifying statements by abusers [20, 21]. Besides the misuse due to the rewards of “feeling high” several studies cite reasons such as use of opioids for self-medicating psychological issues and in response to trauma and life stressors to “dull” the emotional pain, especially in women [22–24]. Among the life events most commonly reported by participants as contributory to their prescription drug abuse were childhood abuse episodes, loss of employment, child custody issues, relationship difficulties, housing instability, and overall discontentment with life. In addition, some used opioids to help them withdraw from other drugs such as cocaine, benzodiazepines, etc.

The utility of these drugs in relieving anxiety and depression implies that there is probably considerable psychopathology in those who are diagnosed with a substance abuse disorder. This is supported by research that has found high rates of psychiatric comorbidity in those who abuse opioids [25] Although it is known that chronic pain is associated with higher anxiety and depression, drug abuse has been found to be significantly higher in those with psychological comorbidities in both sexes [26]. Peer pressure was found to be higher in males compared to females [27]. Animal studies similarly suggest that an animal’s drug use can be affected by that of its cage mate.

These examples show how modification of the social and cultural environment may play a major role in decreasing opioid abuse. Thus, addressing the “why” along with other measures including Prescription Monitoring Programs (PMPs) and legislative crack-down on “pill mills” and “script doctors,” is key in this fight against opioid abuse. While it is true that prescription abuse has been rampant, this problem cannot be resolved by withholding treatment of pain; it needs an understanding of the PK/PD of these drugs to make their use safer.

4. Opioid PK and PD influence abuse potential

The abuse potential of an opioid is dependent on several pharmacologic factors, broadly classified under PK and PD, which ultimately result in achieving high concentrations or high effects at the brain receptors. [28] Thus, brain blood concentrations determined by PK influence exposure to opioids. Furthermore, the opioid receptor ligand interactions and co-administration of other potentiating/antagonizing drugs determine their effects. These factors are tabulated in Table 1. Finally, individual genetic/environmental factors make one susceptible to the likeable effects of the drug and abuse likelihood. In this section, we will discuss the evidence behind the PK-, PD profiles of opioids and the pharmacogenetic factors that play a role in abuse.

Table 1.

Pharmacologic factors affecting the abuse potential of opioids.

Physiochemical and Pharmacokinetic	Pharmacodynamic
Lipophilicity	Receptor affinity
Molecular weight	Dissociation kinetics
Chemical form	Development of tolerance to opioid effects
Absorption rate constant
Elimination rate constant
Cmax
Tmax
Infusion rate
Protein binding
Route of administration
Bioavailability
Volume of distribution

4.1. Pharmacokinetic factors

The physicochemical properties of the drug, route of administration, rate of administration and onset effect rate are key PK properties that influence abuse potential [28]. Among physicochemical properties, low molecular weight and high lipophilicity leads to faster uptake across blood-brain-barrier (BBB) and rapid absorption rate (High Ka) [28]. They contribute to drug effect onset time by altering the rate of absorption of circulating drug across the blood brain barrier due to drug ionization and lipid solubility at physiological pH, with specific examples made of fentanyl, oxycodone and the di-acetylated morphine pro-drug heroin which are known to be highly lipophilic and rapidly absorbed across membranes (The related physicochemical properties of many opioid drug compounds have already been adequately reviewed by Roy et al. [29] and more recently by Mazak et al. [30] and will not be presented further here). A drug with low plasma protein binding will have higher % of free drug in plasma and subsequently in brain, leading to a greater effect. In addition, the chemical form of the drug may affect abuse potential. The effects of cocaine are however similar regardless of whether it is in the form of cocaine hydrochloride or crack cocaine (cocaine base).[31] However, abuse potential of cocaine hydrochloride is different from cocaine sulphate as it has a low melting point due to which it is almost destroyed when smoked.[28]

Opioids are available in many forms and are taken by oral ingestion, snorting by nose or by intravenous injections. Route of administration factors strongly as a determinant of the rate of drug onset due to differences in absorption by membrane location (e.g. pulmonary arteriolar absorption of smoked drugs), and whether absorbed drugs are exposed to first pass metabolism, as may occur with oral administration. In a study conducted in mice, tramadol was administered to B6 mice by intravenous, intraperitoneal, subcutaneous and oral routes difference in C_max and half-life was observed based on route of administration ([32]. Similarly, a drug with high bioavailability upon oral or intranasal administration will achieve higher plasma concentration and is more likely to be abused.

Rate of administration may be an important factor. In a study of intravenously administered morphine, it was observed that faster administration resulted in higher plasma level (than slow administration), greater drug effect, higher opioid agonist response and greater drug liking [33]. Higher opioid doses are associated with higher risk of opioid induced overdose death. This risk reduces in ER formulation of opioids due to lower maximum daily dose In another study involving alprazolam administration to the individuals with history of sedative abuse, an extended release formulation demonstrated lesser abuse potential compared to immediate release product [34]. The ER formulations of hydromorphone and oxycodone are associated with longer time to maximum concentration (T_max) upon consumption of whole tablet, imparting reduced abuse potential [35] [36].

A faster absorption rate may also result in higher drug exposure and greater effects. Though such relationships have not been well explored yet, in a study that compared PK and abuse potential of morphine, extended release morphine and crushed morphine, it was observed that maximum concentration (C_max) and abuse quotient (AQ; C_max/T_max) are strongly correlated with drug liking peak effect (E_max), ‘Overall Drug Liking’ and ‘Take Drug Again at 12 hours’ visual analog scores [37]. A positive association was observed between abuse potential measures with C_max and AQ. The PK parameters were found to be effective predictor of E_max followed by ‘Overall Drug Liking’ and ‘Take Drug Again at 12 hours’ [37]. Maximum effect and time to maximum effect may be important factors determining abuse potential [38]. More studies are needed to characterize how PK-PD affects abuse potential. Such information is valuable to design safer opioids and develop abuse deterrent opioid products. This has been discussed further in later sections. It is notable however that data related to the pharmacology of insufflated prescription opioids is largely lacking at the present time despite the apparent popularity of this modality among opioid abusers.

4.2. Pharmacodynamic factors

There are four major subtypes of opioid receptors, namely delta (δ, DOR), kappa (κ, KOR), mu (μ, MOR) and Nociceptin receptor (NOR / Orphanin FQ receptor). They share a common structural homology – seven transmembrane domains which define a conserved binding pocket – but are divergent in the sequence of their respective extracellular and intracellular peptide sequences, giving rise to differences in ligand binding affinities and downstream signal propagation [39]. The pharmacological characteristics of commonly abused opioids is summarized in Table 2. The current consensus is that activity of the mu opioid receptor is the most salient with regard to both opioid analgesic effect and subjective euphoric experiences associated with habituation and addiction [40]. Recent reviews discuss how MOR and KOR operate within the neurocircuitry of addiction and depression, as well as how variants of mu opioid receptor affect addiction risk [41, 42]. While it is intuitive that relative opioid drug potency (related to receptor binding affinities and drug molecular structure) should be predictive of likeability, several studies have concluded that this is not necessarily the case [43–45]. The rate of drug effect onset plays a bigger role in determining likeability as was demonstrated in a study of morphine infusion rate effect on subjective experience documented by Marsch et al [33]. An additional factor in opioid drug likeability is represented by the presence or absence of negative drug side effects which may occur secondary to opioid receptor subtype specificity and activity, or to off-target effects (e.g. opioid-induced histamine release from mast cells). Perhaps unsurprisingly given empirical and epidemiological observations, several studies comparing the subjective effects of different opioid drugs found significantly fewer, or absence of negative effects associated with the administration of oxycodone in both opioid-abusing and non-abusing cohorts [43, 45, 46].

Table 2: Pharmacological characteristics of commonly abused opioid drugs.

Characteristics of opioid drugs related to abuse liability are given for commonly abused or high-abuse-potential opioids. Among factors thought to influence drug likeability are relative potency (as characterized by opioid receptor kinetics), time to onset of drug effect, and duration of drug effect. Equivalent dosages of drug by route of administration is also provided for consideration (based upon 10 mg intravenous morphine as comparator), although there is considerable yet minor disagreement between available equivalency tables, and inter-individual variabilities in subjective experiences cannot be easily accounted for. Data sources for comparative data are indicated by superscript corresponding to references listed below. The designation of NA indicates that the respective data was not found or was unavailable.

Drug	Receptor Affinity (Ki / nM)[94, 135, 136]			Route of Administration	Equivalent Dose[137]#	Onset[137–141]	Duration[137–141]	Half life[141, 142]
	MOR	DOR	KOR
heroin	see morphine	see morphine	see morphine	insufflation	20–35 mg	10–15 min	3–6 hr	>2–3.5 hr
				smoked	15–25 mg	5–10 min	3–5 hr
				intravenous	5–10 mg	0–5 min	4–5 hr
hydrocodone	11.1	962	501	oral	25 mg	10–20 min	4–8 hr	3.3–4.4 hr
				Intravenous	NA	< 5 min	~ 2 hr
morphine	2.48 ; 14.0	290 ; >1000	46.8 ; 538	oral	25 mg	<30 min	~4 hr	2–3.5 hr
				insufflation	15–20 mg	10–30 min	4–5 hr
				IV / IM	10 m	<1 min	2–4 hr
oxymorphone	0.78	50	137	oral	15 mg	15–30 min	3–4 hr	7–9 hr
				intravenous	1 mg	NA	NA
oxycodone	8.69	901	>1000	oral	12 mg	10–15 min	3–6 hr	2–3 hr
				intravenous	8.4 mg[143]	< 5 min	~ 6 hr
hydromorphone	0.47	18.5	24.9	Oral	5 mg	15–30 min	4–5 hr	2–3 hr
				intravenous	2 mg	<5 min	2–3 hr
fentanyl	0.39	>1000	255	intranasal	25–50 μg	5–15 min	1–4 hr	3–4 hr
				intravenous	0.1 mg	2 min	~ 1 hr

^#ClinCalc (online resource) accessed Oct. 2019 at https://clincalc.com/Opioids/

Another aspect of opioid epidemic is adulteration of opioid (especially heroin) and non-opioid illicit drugs with fentanyl and its analogues. Since fentanyl is 30 to 50 times more potent than heroin, fentanyl adulteration greatly increases risk for overdose mortality[47]. In opioid related overdose deaths in Massachusetts, toxicology was positive for fentanyl in 75% of cases.[48] Similar reports have been reported from Kentucky, Milwaukee and other states[49, 50]. However, due to redistribution phenomena, post mortem analyses of fentanyl can be difficult to interpret, and can lead to under-reporting.[51]. Novel compound identification is aided by nontargeted testing with LC-HRMS (liquid chromatography high resolution mass spectrometry). Due to high affinity for opioid receptors and increased central depression, fentanyl containing designer drugs are a major public health concern requiring vigilance from law enforcement, government agencies, chemists, pharmacists, and physicians.[52]

4.3. Genetics, epigenetics and pharmacogenetics of opioid abuse

4.3.1. Genetics

An important component of risk is the pharmacogenetic risk for opioid tolerance, abuse and misuse. Family, twin, and adoption studies have consistently reported that genetic factors contribute to dependence behavior and relapse [53, 54]. In fact, heritability of liability usually ranges from ≈ 25% to 80%. Additionally, there is a reported 8-fold increased risk of drug disorders among the relatives with history of drug disorders across a wide range of substances, including opioids, cocaine, cannabis, and alcohol [55]. Associated environmental factors also suggest a role for epigenetic factors playing a role due to their influence on gene expression. In fact, environmental influence accounted for 33.9% of the total variance in risk for drug dependence [56].

The majority of early genetic association studies for opioid dependence were retrospective, case-control studies that compared genotype and allele frequencies between cases of opioid dependence and controls [57]. Limitations of several of these studies were that they excluded individuals with major psychiatric disorders and were mostly conducted in modestly sized Caucasian cohorts. Two large candidate studies with sample sizes>500 cases were conducted in European American and Han Chinese cohorts [58, 59]. These studies evaluated gene variants in opioid receptor genes and dopamine (dopamine receptor D2/DRD2 and dopamine transporter gene DAT1) pathways. They found DRD2 TaqI A1 allele carriers had higher risk of heroin abuse and reported positive associations between delta opioid receptor (OPRD1) variants and substance use disorder. Similarly, other human and animal studies have shown association of dopamine receptor D2, D3 and D4 variants associated with opioid addiction, and treatment outcomes.[60, 61] Using positron emission tomography, D2/3 receptor availability was shown to be significantly reduced in the nucleus accumbens of impulsive rats with higher rates of self-cocaine administration.[62] Variants of opioid receptor genes including mu (OPRM1) and kappa (OPRK1) opioid receptors have also been linked to opioid dependence in subgroup analyses by ethnicity (Hispanic) as they alter binding and signal transduction. [63, 64] Besides opioid and dopamine pathways, variants in neurotrophic factors (brain-derived neurotrophic factor/BDNF, neurexin-3/NRNX3), involved in synaptic plasticity have also been implicated in opioid dependence [65, 66].

OPRM1 variant associations have also been confirmed using genome wide association studies (GWAS). [67] Using meta-analysis, a GWAS in 3058 opioid-exposed European Americans was conducted for opioid dependence [68]. They found a variant on chromosome 15, rs12442183, near RGMA (encodes repulsive guidance molecule A, a central nervous system axon guidance protein), associated with opioid dependence. They also confirmed upregulation of gene expression in the striatum in mice homologous for Rgma. Another study including 5432 African Americans and 6788 European Americans reported small effect in potassium (KCNC1 (potassium voltage-gated channel subfamily C member 1) and KCNG2 (potassium voltage-gated channel modifier subfamily G member 2)) and calcium-channel subunit genes [69]. In addition, CNIH3 gene (cornichon family AMPA receptor auxiliary protein 3), which codes for AMPA protein, and LCE3B/3C (late cornified envelope 3B/3C) genes that play roles in immune regulation, have also been reported to be associated with opioid dependence. [70, 71]

Genes influencing methadone PK have been studied. A systematic review and meta-analysis by Dennis et. al. [72] concluded that homozygosity for the CYP2B6*6 genotype is associated with higher trough methadone plasma concentrations, suggesting that methadone metabolism is significantly slower in *6 homozygous carriers. This would be important while prescribing methadone for drug addiction programs.

4.3.2. Epigenetic mechanisms

Epigenetic mechanisms contribute to opioid addiction risk. Opioid use promotes higher levels of permissive histone acetylation (H3K27ac in GRIA1, a glutamatergic gene implicated in drug-seeking behavior) [73], lower levels of repressive histone methylation (H3K9me2, in FosB gene – a critical transcription factor that promotes drug addiction) [74] increased DNA methylation patterns [75–77] and non-coding RNA expression, throughout the brain’s reward circuitry. Additionally, studies manipulating epigenetic enzymes in specific brain regions (for example, using non-specific pharmacological inhibitors of histone deacetylases (HDACs)) are investigating causal links between epigenetic modifications and addiction behaviors. Transcriptional regulation by cyclic AMP response element-binding protein (CREB) has also been the focus of study as a mechanism of tolerance to rewarding effects of drugs of abuse [78]. Glutamate signaling and associated synaptic remodeling have also emerged as critical targets for opioid-induced epigenetic and transcriptional changes. A detailed review is presented by Browne et. al. [79].

It is important to understand the role of genetics in opioid addiction and treatment to enable tailored and effective approaches to prevent and treat opioid abuse. It is anticipated that improved understanding of epigenetic mechanisms, in combination with bioinformatics will help identify differentially regulated gene networks which in turn will allow unraveling of novel targets for opioid addiction.

5. Pharmacology of major drugs to treat opioid abuse, addiction and overdose (methadone, buprenorphine, naloxone. naltrexone)

First line therapeutics used for the treatment of opioid abuse, dependence and overdose act upon the endogenous opioid receptors, a subgroup of the class A (Rhodopsin) family of inhibitory G protein-coupled receptors expressed broadly throughout the nervous system, peripheral neurons, and within the digestive tract. Relative to the other subtypes, mu receptor agonism within respiratory centers of the brain stem is believed to underlie opioid-induced respiratory depression which represents the primary cause of mortality associated with opioid overdose. Among the downstream pathways of mu receptor activation, signaling through β-arrestin has been shown to correspond with respiratory depression and other opioid side effects, whereas analgesic activity is mediated through G-protein-coupled pathway activation. This bifurcation of opioid effect in downstream signaling has prompted efforts to investigate and develop pathway-biased mu receptor agonists with the goal of improving opioid analgesic drug efficacy and safety [80]. Studies have shown also that delta receptor activity may potentiate downstream effects of mu-signaling and may impact the development of opioid tolerance [81, 82] whereas kappa opioid agonists characteristically produce dysphoric experiences, sometimes accompanied by hallucination, and have been a subject of interest for the treatment or prevention of addictive disorders [39, 83]. It is important to note that agonist signaling through the NOR subclass receptor may be another important target for treatment of addictive disorders, however fewer studies have investigated binding at this receptor for many first line therapeutics.

For the purpose of this paper, the pharmacology of the four most prescribed drugs, namely methadone, buprenorphine, naloxone and naltrexone are discussed in relation to their binding and activity at mu, delta and kappa opioid receptors. Summary data related to the receptor affinities of each are also presented in Table 3.

Table 3: Pharmacological characteristics of drugs commonly used for the treatment of opioid dependence and overdose.

Receptor binding affinities and binding function (Activity) are presented for methadone, buprenorphine, naloxone and naltrexone at mu (MOR), delta (DOR), and kappa (KOR) opioid receptors. The analogous data are also give for both Fentanyl and Morphine as comparators representing the two major archetypal mu receptor agonist drugs. For certain drugs, values are presented from two seminal studies by (1) Raynor et al., Mol Pharmacol; 45(2):330–4 (1994) and (2) Codd et al., J Pharmacol Exp Ther; 274(3):1263–70 which determined receptor binding affinities in recombinant human opioid receptors and isolated rat opioid receptors respectively. Where binding data has been given for an active enantiomer of a drug employed as a racemic mixture (+/−), the binding of the racemic drug is inferred as double of the active enantiomer binding affinity. Receptor Activity for each drug is presented as AGN (agonist), pAGN (partial agonist) and ANT (antagonist).

Compound	Receptor Affinity (Ki / nM) | Receptor Activity
	MOR		DOR		KOR
Fentanyl	0.39¹	AGN	>1000¹	AGN	255¹	AGN
(+/−) Morphine	2.482 ; 14.0¹	AGN	2902 ; >1000¹	AGN	46.82 ; 538¹	AGN
(+/−) Methadone	0.72¹ ; 1.702	AGN	4352 ; >1000¹	AGN	4052 ; >1000¹	AGN
Buprenorphine	4.182	pAGN	25.82	ANT	12.92	ANT
(+/−) Naloxone	1.122 ; 1.86¹	ANT	34.0¹ ; 73.02	ANT	4.60¹ ; 9.822	ANT
Naltrexone	0.082 ; 1.00¹	ANT	8.022 ; 149¹	ANT	0.512 ; 3.90¹	ANT

5.1. Methadone

Methadone is a synthetic mu-opioid receptor agonist originally approved for use as an analgesic and antitussive by the US Food and Drug Administration (FDA) in 1947. Structurally unrelated to morphine, methadone is available for use as a racemic mixture of two enantiomers: levomethadone R(–), which binds strongly to the opioid receptors as an agonist, imparting most of its analgesic affect; and dextromethadone S(+), which binds antagonistically to N-methyl D-aspartate (NMDA) receptors which is believed to confer efficacy against some forms of neuropathic pain which may otherwise be non-responsive to opioid analgesics. Although methadone still carries an indication for the treatment of moderate to severe pain, it was adopted circa 1964 for use in opioid detoxification and maintenance therapies due to what were considered at the time to be favorable pharmacological characteristics [84]. Among these considerations are a longer duration of action, lack of an active metabolite, and purportedly lower subjective experience of euphoria and development of tolerance relative to other strong mu-opioid agonists. At the present time, methadone is available in several oral forms for treating opioid addiction using once-daily dosing. These include tablets, liquid-dispersible tablets, and as a solution which allows for highly flexible dosing. Despite being regarded as an effective therapeutic, methadone prescribing information carries a black box warning for potentially fatal respiratory depression and cardiac arrhythmias due to QT interval prolongation. Respiratory depression caused by methadone is also considered to be problematic as it may develop later in treatment and persist beyond the therapeutic effects owing to an extended metabolic half-life (8–59 hours) [85]. The wide range in observed methadone half-life serves to underline highly variable drug bioavailability and PK between individual patients, largely attributed to the involvement of highly pleomorphic enzymes, including P-glycoprotein, CYP3A4 and CYP2B6, in the pathways of methadone distribution and elimination. For these reasons, methadone as used for detoxification or maintenance therapy may be difficult to titrate initially, and the required dosage for treating individual patients may vary between 10–220 mg daily [85]. Due to the need for careful titration and patient monitoring, clinical use of methadone for opioid detoxification and maintenance therapy is restricted to oral formulations and must be administered only by certified opioid treatment programs in the United States, as outlined in Title 42 of the Code of Federal Regulations, Part 8 (42 CFR Part 8).

5.2. Buprenorphine

Buprenorphine is a semisynthetic opioid drug originally approved in 1981 for treatment of moderate to severe pain, and later in 2002 for the treatment of opioid dependence. The PD properties of buprenorphine are somewhat unique in that it functions as a partial agonist at mu opioid receptors but has antagonistic activity at both delta and kappa receptors. Although the mu agonist effect of buprenorphine is less relative to other opioid analgesics, it binds with high affinity to this receptor type, conferring competitive inhibition against other opioid drugs and partial resistance to the reversal drug naloxone [86]. Additionally, its use is understood to produce a ceiling effect at moderate doses with regard to the experience of euphoria and the induction of respiratory depression [87], and by virtue of relatively slower dissociation kinetics, it has an extended duration of action allowing for daily or less-than-daily dosing. Buprenorphine undergoes extensive first pass metabolism which effectively renders oral administration impractical, despite the finding that the primary metabolites buprenorphine-3-glucuronide and norbutrenorphine-3-glucuronide retain biological activity [88]. This observation is likely to be explained by the high degree of buprenorphine metabolite elimination through the biliary pathway. Due to a high lipophilicity however, buprenorphine has appreciable systemic bioavailability when administered via the oral mucous membranes and is marketed in both sublingual tablets and buccal films either alone (for clinical use) or in combination with the mu-receptor antagonist naloxone to discourage parenteral abuse in outpatient settings. The usual dosage range for maintenance therapy by buccal or sublingual route is between 4–24 mg buprenorphine in combination with 1–6 mg naloxone daily. Buprenorphine is also available as an extended release subcutaneous injection for monthly use, and as an implantable device which provides treatment for up to six months.

5.3. Naloxone

Naloxone is a synthetic derivative of the analgesic drug oxymorphone which is used to reverse the effects of opioid drugs on the central nervous system. As a nonspecific opioid receptor antagonist, naloxone is available as a racemic mixture where the (+) enantiomer does not bind appreciably to opioid receptors at therapeutic dosages, whereas the (−) enantiomer has relatively strong binding affinity for mu, and to a lesser extent, delta, and kappa opioid receptors. Binding affinity for the mu opioid receptor is similar to or stronger than most opioid analgesics, allowing for efficient competitive inhibition against their binding. However, due to rapid receptor dissociation kinetics and active transport out of the brain by p-Glycoprotein, naloxone possesses a short elimination half-life of approximately 30 minutes. As many opioid drugs have a longer duration of activity, multiple doses or continuous infusion of naloxone may be required to adequately reverse life-threatening opioid induced respiratory depression. Extensive first-pass metabolism via glucuronidation limits the systemic bioavailability of naloxone to the extent that oral use is impractical outside of treatment of opioid-induced side effects in the digestive system. [89, 90] As sublingual and buccal bioavailability are also negligible, naloxone has found use in combinatory formulations for preventing parenteral abuse of opioid analgesics and the drugs used to treat opioid addiction. Naloxone has also been found to be a relatively safe drug when used in dosages up to 10 mg, however some degree of care must be exercised with regard to route of administration and the initial dosage used in order to prevent precipitation of potentially life-threatening withdrawal symptoms in opioid dependent subjects. Naloxone has been approved for opioid reversal use by multiple parenteral routes, including intravascular (IV), intramuscular (IM), and subcutaneous (SC) injection, and also as an intranasal spray. IV injection of naloxone affords rapid onset of opioid reversal (2 minutes) relative to IM and SQ routes (<8 minutes) and intranasal (8 minutes).[91, 92] As compared to parenteral routes, the bioavailability of intranasal naloxone is somewhat reduced and may also vary according to individual differences in access to or patency of the absorptive intranasal epithelia. Naloxone has been approved for community or outpatient use by auto-injector for IM and SC application at dosages of 0.4 or 2 mg, and by intranasal application at dosages of 2 or 4 mg. As reviewed by Ryan and Dunne, several usability studies have reported a greater than 90% rate of successful application of the approved intranasal and auto-injector formulations by untrained study participants [93].

5.4. Naltrexone

Naltrexone, is a synthetic derivative of oxymorphone acts as a potent and nonspecific opioid receptor antagonist, with highest affinity for mu receptors, followed closely by kappa, and to a much lesser extent, delta receptors [94]. It differs structurally from naloxone by only a minor substitution at the tertiary amine alkyl group. This relatively small structural change appears to impact the pharmacology of the compound across several dimensions. The primary pharmacologic activity of naltrexone is to competitively block receptor binding of opioid drugs, thereby inhibiting their subjective effects, and is also believed to concomitantly reduce treatment-associated dysphoria via virtue of kappa receptor antagonism. Naltrexone is well absorbed from the gastrointestinal tract, and is subject to considerable first pass metabolism, primarily by hepatic conversion to the active metabolite 6β-naltrexol via dihydrodiol-dehydrogenase enzyme activity [95, 96]. Although 6β-naltrexol has diminished antagonist activity, it is present in significantly higher (plasma) concentrations than the parent compound following oral administration. As compared to naloxone, the relatively long metabolic half-lives of naltrexone and 6β-naltrexol (4 and 13 hours respectively) substantially increase the risk associated with the precipitation of withdrawal symptoms. For this reason, naltrexone therapy is not initiated until after the patient has fully withdrawn from other opioid drugs [97]. Naltrexone is available in oral tablets (50 mg) for once daily dosing, and as a suspension for intramuscular depot injection (380 mg) every four weeks.

5.5. Drug-drug interactions involving drugs used to treat opioid abuse

A final topic of note relates to the potential for drug-drug interactions involving pharmacotherapeutics for the treatment of opioid use disorder. A primary concern is the potential for interaction with antiviral therapeutics (both direct acting and antiretroviral agents) and additionally other pharmacologically active compounds that may find higher use among opioid dependent populations. For review of antiviral medication interactions with methadone and buprenorphine maintenance therapy, we direct the reader to the works of Bruce et al. [98] and Meemken et al. [99]. Owing to its status as a substrate for P-glycoprotein and multiple Cytochrome P450 enzymes, a large number of studies have looked at the potential for interactions of methadone co-medication with somewhat varied results. As reviewed by Volpe et al. [100] drugs inhibiting CYP3A4 activity - which comprise a substantial portion of prescribed antiviral compounds - may increase systemic methadone exposure and associated side effects, whereas inducers of CYP2B6 activity (e.g. nevirapine, efavirenz, and ritonavir) may reduce methadone exposure and necessitate dosage adjustment to prevent emergence of withdrawal symptoms. Outside of antiviral therapy, consideration of dose adjustment may be required in the setting of polypharmacy of methadone with other medications known to induce Cytochrome P450 enzyme activity and/or prolongation of QT interval [101]. In contrast to methadone, there is far less evidence of clinically significant interaction between buprenorphine, naloxone, or naltrexone when co-administered with other medications - a finding which may reflect the lower contribution of Cytochrome P450 activity towards drug elimination among these compounds. Of these three, only buprenorphine has been shown to participate in Cytochrome P450-mediated metabolism in the form of N-dealkylation, primarily to the active metabolite norbuprenorphine, through the activity of CYP3A4/3A5 and CYP2C8 [88, 102]. In contrast, neither naloxone nor naltrexone are significantly metabolized through Cytochrome P450 activity which likely accounts for the dearth of investigations into their interaction with other drugs. One in vitro study has reported an inhibitory effect of naltrexone hydrochloride on the activities of Cytochrome P450 enzymes 1A2, 2C9, 2D6 and 3A4 [103]; however, with the exception of CYP2C9, clinically-relevant effect was not apparent at therapeutic naltrexone concentrations. Regarding buprenorphine interactions, a pair of studies by Fihlman et al. have found that concomitant administration of voriconazole, a strong inhibitor of CYP3A enzymes, with oral [104] and sublingual [105] buprenorphine significantly increased buprenorphine and norbuprenorphine exposure, yet similar to prior work indicating decreased buprenorphine exposure with co-administration of efavirenz [106], these studies did not find clinically significant consequences of altered buprenorphine exposure. At odds with the former studies of voriconazole however, a report by McCance-Katz et al. described increased sedation in 30% of study patients receiving buprenorphine/naloxone co-administered with atazanavir or atazanavir plus ritonavir [107], a finding which is corroborated by a case report of excessive sedation in three patients receiving buprenorphine with atazanavir/ritonavir which required a reduction in patients’ buprenorphine dosage [108]. Interaction of buprenorphine and benzodiazepine drugs have also been reported in association with significant morbidity and mortality [109]; however as the study authors discuss, it is more likely that toxicity in this setting results from pharmacodynamic rather than pharmacokinetic interaction. Taken together the existing study data suggest that assessing the impact of CYP3A activity may be warranted when buprenorphine is used concomitantly with other medication, and additionally that caution should be exercised when buprenorphine is used concurrently with central nervous system depressing drugs or in patients suspected of illicit depressant use.

6. Abuse-deterrent formulations and mechanisms

There are seven PK-PD based mechanisms that confer abuse-deterrent properties. [110, 111] First, the drug can be designed with physical or chemical barriers to resist mechanical alternation of medication. One of the most common techniques applied is increasing the tablet tensile strength to resist crushing. One such example is the application of polyethylene oxide polymer in Arymo ER, Hysingla ER, or Opana ER, while others use fat and wax polymers in the tablet’s granules (Vantrela ER). Alternatively, viscous gel formation after aqueous medium exposure can also provide a chemical barrier to deter unintended routes of administration, such as Oxaydo or ADPREM.[38, 112] Secondly, by combining an opioid agonist with an opioid antagonist, one aims to reduce opioid-induced euphoria if intranasal route is administered. There are four opioids with naltrexone added to their formulations (Troxyca ER, Oxytrex, Oxynal, Embeda), while three other opioids utilized naloxone (Targiniq, Suboxone Film, Talwin). Thirdly, a medication can contain aversive substances that decrease its overall likeability for unintended uses. Drugs such as Oxaydo, Roxicodone, or Acurox with niacin can result in nasal irritation that aims to deter intranasal abuses. Also, the medication can have a novel drug delivery system that renders manipulation difficult, such as extended-release depot injections or implants. Fifth, a design of a prodrug or New Molecular Entity Entity, which only becomes bioavailable after conversion to an active form, can avoid releasing medications in an unintended route. New River Pharmaceuticals had proposed lysine-modified opioid prodrug derivatives of oxycodone (NRP-290) and hydrocodone (NRP-369) that aims to deter IV and intranasal abuse. No further information regarding development of these two medications are available after Taketa Pharmaceutical ultimately acquired the company and its pipeline [113]. Sixth, one can design a product with combinations of two or more techniques that hopes to achieve stronger abuse deterrence, such as MNK-812, Targiniq, or Embeda. In the case of MNK-812 (SpecGx/Mallincroft), it is a reformulation version of Roxicodone that is hard to crush and yields low syringeable oxycodone after crushing (https://www.fda.gov/media/121222/download). In addition, it possesses multiple gelling agents, which requires a sophisticated method such as large volume, large needle, high temperature, and prolonged extraction time greater than 1 hour in order to challenge its ADF property for IV abuse. Finally, it decreases subjects’ willingness to snort repeatedly because the aversive agents cause pain and burning during intranasal abuse. Unfortunately, FDA ultimately rejected the ADF replacement of Roxicodone in December, 2018 with no further available information from Mallinckrodt [114]. Lastly, novel technologies that are not listed from the above descriptions, such as G protein selective antagonism at the delta or mu-opioid receptors, or novel substance P receptor modulators, aim to provide analgesia while decrease abuse potentials [115]. Description of available ADFs by mechanisms and outcomes are presented in Table 4.

Table 4: Abuse deterrent formulations and mechanisms of action.

Abuse-Deterrent Technique: 1. Physical or 2. chemical barrier to resist mechanical alternation of medication. 3. Agonist/antagonist combination to reduce opioid-induced euphoria if the orally administered medication is used via nasal/IV route; 4. Aversive substances that decrease drug appeal for unintended uses. 5. Novel delivery system that makes manipulation difficult once administered. 6. New prodrug formulation.

Works Cited	Pharmaceutical	Formulation	Medication component	FDA approval ADF label	US availability	Abuse-Deterrent Technique						Comment
						1	2	3	4	5	6
7	Egalet Corporation / Acura Pharmaceuticals	Oxaydo	Oxycodone IR	2015	✓		✓		✓			viscous gel forming agent deter IV abuse. Aversive agent cause nasal irritation to deter IN abuse
5	SpecGx / Mallinckrodt plc	Roxicodone	Oxycodone IR	none	✓	✓	✓		✓			Physical manipulation resistant. viscous gel forming agent deter IV abuse. Aversive agent cause nasal irritation to deter IN abuse
18	Daiichi Sankyo Company, Limited	RoxyBond	Oxycodone IR	2017	N/A	✓	✓					Physical manipulation resistant. Chemical extraction and dosage dumping hindered.
8,9	Acura Pharmaceuticals, Inc	LTX01 & LTX 02	Oxycodone IR	none	N/A							When ingest in large quantities, micro-particle ingredients bind tablet matrix to slow the release of active ingredients. Insoluble nasally.
19	Acura Pharmaceuticals	Acuracet	Oxycodone IR + niacin + APAP	none	N/A	✓			✓			viscous gel forming agent deter IV abuse. Aversive agent cause nasal irritation to deter IN abuse
20	Acura Pharmaceuticals / King Pharmaceuticals	Acurox with niacin	Oxycodone IR + niacin	none	N/A		✓		✓			viscous gel forming agent deter IV abuse. Aversive agent cause nasal irritation to deter IN abuse
1, 2, 3, 21	Purdue Pharma	OxyContin	Oxycodone ER	2010	✓	✓	✓					Physical manipulation resistant. viscous gel forming agent deter IV abuse.
2, 21	Collegium pharmacetuical	Xtampza ER	Oxycodone ER	2016	✓	✓	✓					Microspheres with physical manipulation resistance. Chemical extraction and dosage dumping hindered.
21	Pain Therapeutics	Remoxy	Oxycodone ER	none	N/A	✓	✓					Hard gelatin capsule containing viscous liquid
21	Pfizer	Troxyca ER	Oxycodone ER + naltrexone	2016	N/A			✓				naltrexone is released to counteract the effects of oxycodone.
2, 21	Purdue Pharma	Targiniq ER	Oxycodone ER + naloxone	2014	N/A	✓		✓				Physical manipulation resistant and naltrexone is released to counteract the effects of oxycodone.
21	Labopharm/Paladin	DDS-08B	Oxycodone ER + APAP	none	N/A	✓						Drug still is released slowly even after manipulation
21	Collegium Pharmaceuticals	COL-003	Oxycodone SR	none	N/A	✓						Deters multiparticulate matrix with partcles in waxy excipient base
21	Collegium Pharmaceuticals	COL-172	Oxycodone SR	none	N/A	✓						Multiparticulate matrix with partcles in waxy excipient base
21	Intellipharmaceutics	ReXista	Oxycodone SR	none	N/A	✓						No further description
21	Albert Einstein College of Medicine	oxytrex	Oxycodone + naltrexone	none	N/A			✓				Ultra-low dose naltrexone
21	Elite Pharmaceuticals	OxyNal	Oxycodone SR + naltrexone	none	N/A			✓				naltrexone release when crushed
12	New River Pharmaceuticals	NRP 369	Oxycodone	none	N/A						✓	conditional bioreversible derivative. Lysine-modified
8,9	Acura Pharmaceuticals, Inc	LTX-03	Hydorcodone IR + APAP	none	N/A	✓						When ingest in large quantities, micro-particle ingredients bind tablet matrix to slow the release of active ingredients. Insoluble nasally.
21	Acura Pharmaceuticals, Inc	Vycavert	Hydrocodone IR + APAP	none	N/A	✓						No further description
2	Purdue Pharma	Hysingla ER	Hydrocodone ER	2014	✓	✓	✓					Physical manipulation resistant. Chemical extraction and dosage dumping hindered.
2	Teva Pharmaceuticals	Vantrela ER	Hydrocodone ER	2017	N/A	✓	✓					Physical manipulation resistant. Chemical extraction and dosage dumping hindered.
21	Egalet Corporation	Egalet Hydrocodone	Hydrocodone ER	none	N/A	✓						Non-erodible shell that is water-impermeable with erodible matrix cover
11	New River Pharmaceuticals	NRP 290	Hydrocodone	none	N/A						✓	conditional bioreversible derivative. Lysine-modified
2	Alpharma	Embeda	Morphine ER + naltrexone	2014	✓	✓		✓				Sequesttered naltrexone core surrounded by morphine
2	Daiichi Sankyo Company, Limited	MorphaBond	Morphine ER	2015	✓	✓	✓					Physical manipulation resistant. Chemical extraction and dosage dumping hindered.
2	Egalet Corporation	Arymo ER	Morphine ER	2017	N/A	✓	✓					Physical manipulation resistant. viscous gel forming agent deter IV abuse.
10	Egalet Corporation	ADPREM	Morphine	none	N/A		✓					Non-erodible shell water-impermeable with erodible matrix cover
21	TheraQuest Biosciences	TQ-1017	Tramadol ER	none	N/A	✓						Hydration creates viscous substance
21	TheraQuest Biosciences	TQ-1015	Oxycodone ER	none	N/A	✓						Physical manipulation resistant.
13	Collegium Pharmaceuticals	Nucynta ER	Tapentadol ER	2011	✓	✓						Physical manipulation resistant.
21	Neuromed/Covidien	Exalgo ER	Hydromorphone ER	2010	✓	✓						Osmotic delivery system / OROS push-pull technology
8,9	Acura Pharmaceuticals, Inc	LTX-04	Hydromorphone IR	none	N/A							When ingest in large quantities, micro-particle ingredients bind tablet matrix to slow the release of active ingredients. Insoluble nasally.
16	Titan Pharmaceuticals Inc	Probuphine	Buprenorphine	2016	✓					✓		Subcutaneous implant
17	neuromed/Covidien	Sublocade	Buprenorphine	2017	✓					✓		Subcutaneous implant
15	Reckitt Benckiser	Suboxone Film	Buprenorphine + naloxone	none	N/A			✓				Injection with suboxone will cause withdrawal signs and symptoms from naloxone
4	Endo Pharmaceuticals	Opana ER	Oxymorphone	none	✓	✓	✓					Physical manipulation resistant. Gelling agent resist IV abuse.
21	TheraQuest Biosciences	TQ1020	Levorphanol ER	none	N/A	✓						No further description
21	Sanofi-Aventis	Talwin	Pentazocine + naloxone	none	N/A			✓				naltrexone release with IV administration
6	Nektar Therapeutics	NKTR-181		none	N/A						✓	Long acting selective mu-opioid agonist with reduced rate of CNS permeability. FDA rejected its NDA application on 1/2020.
22	Trevena	TRV250	Ongoing study		N/A							G-protein selective agonist at delta receptor.
22	Trevena	TRV734	Ongoing study		N/A							G-protein selective agonist at delta receptor.
22	Trevena	TRV045	Ongoing study		N/A							Novel non-opioid S1P receptor stimulation in modulating neurotransmission and membrane excitability without immune-suppression

Note: IR: Immediate release. ER: Extended release. SR: Sustained release. APAP: acetaminophen.

Reference:

¹Timeline of Selected FDA Activities and Significant Events Addressing Opioid Misuse and Abuse. (2019, September 25). In U.S. Food & Drug Administration. Retrieved from https://www.fda.gov/drugs/information-drug-class/timeline-selected-fda-activities-and-significant-events-addressing-opioid-misuse-and-abuse

²Litman, R. S., Pagan, O. H., & Cicero, T. J. (2018, May). Abuse-deterrent Opioid Formulations. Anesthesiology, 128(5), 1015–1026.

³U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). (2017, November). In U.S. Food & Drug Administration. Retrieved from https://www.fda.gov/media/96643/download

⁴https://www.drugs.com

⁵https://www.fda.gov/media/121222/download

⁶https://www.nektar.com/pipeline/rd-pipeline/nktr-181

⁷http://investors.acurapharm.com/news-releases/news-release-details/acura-pharmaceuticals-advances-ltx-03-and-its-limitxtm

⁸http://acurapharm.com/otherproductsindevelopment/

⁹https://www.sec.gov/Archives/edgar/data/786947/000114420415056790/v421134_ex99-1.htm

¹⁰https://www.sec.gov/Archives/edgar/data/1586105/000104746915002296/a2223665z10-k.htm

¹¹http://www.nrpharma.com/products/NRP290.htm

¹²http://www.nrpharma.com/products/NRP369.htm

¹³Nucynta ER abuse profile: an evaluation of abuse and route of administration among individuals receiving substance abuse treatment.

¹⁴NECEPAC ADF Draft

¹⁵https://www.suboxone.com/treatment/suboxone-film

¹⁶https://www.fda.gov/news-events/press-announcements/fda-approves-first-buprenorphine-implant-treatment-opioid-dependence

¹⁷https://www.sublocade.com/how-sublocade-works

¹⁸https://www.fda.gov/media/121222/download

¹⁹http://www.annualreports.com/HostedData/AnnualReportArchive/a/NASDAQ_ACUR_2009.pdf

²⁰http://acurapharm.com/products/acurox-tablets/

²¹Raffa, R.B. Designing Opioids That Deter Abuse.

²²https://d1io3yog0oux5.cloudfront.net/_9a5b3f6942e7dadc825709b2c2a32d9e/trevena/db/707/6063/pdf/1.09.20-TRVN_overview_nonconf_JPM_vF.pdf

6.1. Cost-effectiveness of ADFs

Many ADFs are available in the market, but their uses are still limited. One of the major limitations in widespread use of ADFs is the high price compared to generic opioid products. For example, the cost of the approved abuse-deterrent morphine products (Embeda, MorphaBond, and Arymo ER) is in the range of $560 to $1000 for a month supply, compared to $40 for monthly supply of generic extended-release morphine pills [116]. Thus, the cost-effectiveness of the ADFs have been questioned. Using administrative claims from beneficiaries covered by large self-insured companies throughout the country, it was reported that abusers used US$10,627 in per-patient incremental annual healthcare costs as well as US$1,244 in excess annual work-loss costs compared to non-abusers. [117] The Institute for Clinical and Economic Review (ICER) abstracted evidence from available clinical and observational studies reporting abuse related end-points and evaluated cost-effectiveness in a hypothetical cohort model of 100,000 non-cancer chronic pain patients. They found that use of ADF opioids prevented 3,100 new cases of abuse per 100,000 patients treated over five years, with a small (0.5; overdose deaths decreased from 1.77 to 1.25 with use of ADF opioids) decrease in overdose related deaths. [117, 118] However, there is a mixed Real World Evidence to suggest that ADF opioids reduce overall abuse and overdose fatality [See Table 5]. Based on evaluation of 16 randomized control trials and one prospective cohort study, the ICER concluded that all ADFs decrease abuse potential, such as overall drug liking and tampering. [118] However, 29 studies found that reformulated OxyContin is associated with significant opioid diversion, such as increased abuse rates and overdose fatality of heroin and ADF opioids other than OxyContin. [118] Thus, ADF opioids are not conclusively superior for its overall health benefit, but cost patients and the health system significantly more to non-ADF opioids. Overall estimated health care cost is an additional $511 million over five years despite a decreased cost of $214 million was found related to preventing new cases of opioid abuse using ADF-opioids. [118] A major contributing factor affecting cost-effectiveness is the high ADF opioid drug cost, which nearly doubled the overall prescription opioid costs by $644 million. [118] Sensitivity analyses suggested that cost neutrality can only be achieved with a 39% discount in ADF opioid prescription pricing. (From $11.6 to $7.04 per day, at 90mg MED per day)[118]

Table 5:

Evidence for and against effective opioid abuse deterrence from use of available abuse deterrent formulations (ADFs). Drug liking is scaled from 0 to 100. Doctor shopping is defined as the practice of engaging multiple prescribers and/or pharmacies to obtain excess drugs that can be diverted for non-medical use. Diversion is defined as any intentional act that results in transferring a prescription medication from lawful to unlawful distribution or possession.

Outcome	Findings
Overall Drug Liking	8 RCT found significantly lower levels of oral abuse potentials such as drug liking for intact or crushed ADF-opioids vs. non-ADF opioids. (Xtampza ER intact (68.8) vs. xtampza ER crushed (73.4) vs. oxycodone IR crushed (81.8); Troxyca ER intact (59.3) vs. Troxyca ER crushed (74.5) vs. oxycodone IR crushed (89.8); Targiniq ER intact (54.7) vs. Targiniq ER crushed (54.6), vs. oxycodone IR solution (77.9); Hysingla ER intact (63.3) vs. Hysingla ER crushed (69) vs. hydrocodone IR crushed (94), Vantrela ER intact (53.9) vs. Vantrela ER crushed (66.9) vs. Hydrocodone IR (85.2); Embeda crushed (65.2) vs. Morphine ER crushed (80.8); Embeda intact (67.6) vs. Embeda crushed (68.1) vs. Morphine ER crushed (89.5); Arymo ER intact (62) vs. Arymo ER crushed (67) vs. Morphine ER crushed (74)) [1–8] 7 RCT found significantly less likely to re-take for intact or crushed ADF-opioids vs. non-ADF opioids of the same class. (Xtampza ER intact (70.2) vs. xtampza ER crushed (73.7) vs. oxycodone IR crushed (76.2); Troxyca ER intact (48.7) vs. Troxyca ER crushed (72.5) vs. oxycodone IR crushed (81.5); Targiniq ER intact (38.5) vs. Targiniq ER crushed (32.6), vs. oxycodone IR solution (61.4); Hysingla ER intact (32.6) vs. Hysingla ER crushed (43) vs. hydrocodone IR solution (86.7), Vantrela ER intact (46.4) vs. Vantrela ER crushed (58.7) vs. Hydrocodone IR (75.2); Embeda crushed (57.7) vs. Morphine ER crushed (70.7); Arymo ER intact (56) vs. Arymo ER crushed (61.5) vs. Morphine ER crushed (67.5)) [1–8]
	7 RCT found significantly lower levels of oral abuse potentials such as drug liking for intact or crushed ADF-opioids vs. non-ADF opioids. (Troxyca ER (60.5) vs. oxycodone IR (92.8); Targiniq ER (59.1) vs. oxycodone IR (94.8); Hysingla ER (66.8) vs. Hydrocodone (90.4); Vantrela ER (72.8) vs. Hydrocodone (90.4); Embeda (69.6) vs. Morphine ER (87.6); Morphabond ER (71.1) vs. Morphine ER (84.8); Arymo ER (52.5) vs. Morphine ER (77.5)) [9–17] 8 RCT found significantly less likely to re-take for intact or crushed ADF-opioids vs. non-ADF opioids of the same class. (Oxycontin crushed (64) vs. original Oxycontin crushed (89.6) vs. Oxycodone IR powder (86.6); Xtampza ER (47.8) vs. oxycodone IR (71.3); Troxyca ER (58.9) vs. oxycodone IR (88.4); Targiniq ER (42.6) vs. oxycodone IR (93.6); Hysingla ER (34.6) vs. Hydrocodone (83.9); Embeda (60.6) vs. Morphine ER (84.9); Arymo ER (50) vs. Morphine ER (73)) [9–17]
Tampering	1 prospective cohort study found less tampering potential with the reformatted Oxycontin compared to original Oxycontin. (easy to cut-up: 21% vs. 79%, p<0.05; easy to dissolve (14% vs. 74%, p<0.01; unpleasant to tamper and inject: 5% vs. 50%, p<0.01) [18]
Real World Evidence of Abuse	16 studies found reduced rate of abusing reformulated OxyContin (−38%, −75%, −55%, −42%, −30%, −37%, −41%, −22%, −48%, −28%, −28%, −36%, −35%, −55%, −12%, −57%). 13 studies found overall increased rate of abusing other prescription opioids (oxymorphone ER: +38%, +246%, +191%, +236%; morphine ER: +44%, non-significant in three other studies; oxycodone IR: +20%, +36%, +23%, all other opioids: −33%, −7%, +16%, +5%, −3%, non-significant in one other study). 4 studies found increased rate of abusing heroin (+100%, +78%, −11%, +42%). [19–30]
	3 studies found reduced non-oral reformulated Oxycontin abuse rate (snort: −28%, −51%; inject: −20%, −22%; smoke: −2%, −10%) but mixed effect in oral reformulated Oxycontin abuse rate (−71%, +21%, +26%). 2 studies found different abuse patterns with other opioid products. No change in route of administration was noted with ER morphine. ER oxymorphone showed significantly increased snorting (+7%) and injection (+7%) and significantly decreased oral route abuse (−8%). [20, 23, 25]
Overdose and Fatality	5 studies suggested a decline in overdose rate (−34%, −20%, −85%, −87%), 2-year overdose fatality rate (−56%, −65%), and 3-year overdose fatality rate (−85%, −87%) after OxyContin reformulation. However, heroin overdose rate and overdose fatality increased (23% and 310% respectively), while other opioids (morphine ER, oxymorphone ER, oxycodone IR, hydromorphone IR, ilicit drugs) showed no statistically significant changes in overdose and overdose fatality rate. [21, 31, 32, 33, 34]
Doctor shopping	2 studies reported a 50% reduction in doctor-shopping after OxyContin reformulation, but an increase in doctor-shopping for oxycodone IR (5%), hydromorphone IR (25), and oxymorphone ER (66%). [35, 36]
Diversion rate	3 studies suggested a decrease in population adjusted change in diversion (−53%, −89%, −66%, all statistically significant), sale (−24%), and dispensing rate (−39%) of OxyContin after OxyContin reformulation. During the same study periods, other opioids had inconsistent change in diversion rates (−6%, −27%, +6%, all not statistically significant), but increased sales (11%). [19, 20, 21]
Conclusion: Overall, despite a decrease in abuse potential for all abuse deterrent formulations, there is only mixed real-world evidence to suggest that ADFs reduce overall abuse and overdose fatality. Thus, there is not sufficient evidence to conclusively determine the superiority of their health benefit.

7. Conclusion

The cost of the opioid crisis is very high for American society. Apart from financial loss and health issues, it is leading to broken families, newborns with withdrawal symptoms, adolescent growing without parental care and higher fraction of population incarcerated. An in-depth understanding of the PK-PD of abused opioids is necessary for the development of safer opioids. The PK properties contributing towards the abuse potential of opioids are the rapid absorption, high lipophilicity, low molecular weight, rapid accumulation of drug in specific brain region, high bioavailability upon administration by other routes, low protein binding, faster infusion rate, high C_max, (C_max/T_max) ratio, poor clearance, short half-life and low volume of distribution. Thus, an ideal ADF should have low absorption rate constant, lower C_max to limit uptake and high plasma concentration, as drugs with lower C_max are less likely to be misused, and lower abuse quotient (C_max/T_max). The 5-point strategy initiated by the HHS in 2017 to combat the opioid crisis encompasses better preventive, treatment and recovery services, better data, better pain management, better availability of overdose-reversing drugs and better research. These efforts will need to be sustained to successfully combating this problem.

8. Expert opinion

Awareness, education and de-stigmatization of addiction as a disease of decision-making with genetic susceptibility is key for the success of efforts against the opioid crisis. The limited repertoire of strong analgesics without abuse liability makes effective pain management a difficult task. Current clinical practice remains rooted in trial and error using only patient weight as a factor in dosing. Most opioids and analgesics especially in the pediatric age group remain off-label as there are major information gaps informing PK of opioids in children. There is also a dearth of translational PK-PD models incorporating genetics available for clinical implementation. Another important and relevant pediatric topic not covered in this review is neonatal abstinence syndrome (NAS), which develops from postpartum cessation of in utero exposure to opioids, in infants born to mothers with opioid abuse or on a methadone maintenance program.[119] The incidence of NAS in the United States was estimated to be 3.9 per 1000 live births in 2009.[120] In about 55–94% of such infants, NAS may be severe enough to require treatment usually with opioids (morphine, methadone, buprenorphine) and adjuvants (clonidine, phenobarbital) besides conservative measures like breastfeeding. [119] Future drug monitoring programs need to be adapted to real-time technology and feedback incorporated into physiologically based PK-PD for prediction of tailored drug dosing and effects, to prevent over prescribing and abuse liability. Advanced PD biomarkers for pain are needed as current subjective reporting and objective scales may not be reliable or applicable universally. This calls for further evaluation of novel applications of opioid efficacy end-points including pupillometry,[121] galvanic skin resistance, heart rate variability, electroencephalography etc. so that in the future they can be leveraged with the aid of wearable bio-sensors and tele-health advances to help in early diagnosis and treatment of opioid abuse. There is limited evidence that ADF-opioids are effective but not at their current costs. Thus, there needs to be more research in understanding opioid tolerance mechanisms and the neurobiology of addiction to further inform molecular biological advances in development of novel non-mu opioid based ligands. The lack of universal agreement on the definitions of opioid misuse and failure in self-reports at identifying those at risk points to the need for more research in objective biomarkers. Advances in precision health seem to be at the brink of identifying genomic biomarkers to stratify abuse-risk. However, this remains unproven and there need to be further studies rigorously evaluating the effect of precision medicine in driving down abuse to enable changes in healthcare policies conducive to genomic testing. Genomics also has the potential to leverage functional differences in genetic susceptibility to improve pharmacological responses for treatment of addiction.[122] Newly designed opioid agonists based on biased targeting of a selective downstream signal transduction pathway (such as G-protein signaling, beta-arrestin recruitment and receptor internalization) have been developed. [123, 124] There are concerted efforts studying opioid free anesthesia/analgesia techniques such as cryoneurolysis,[125] invasive neurosurgical procedures such as deep brain stimulation[126] and transcranial magnetic stimulation[127] targeting the reward circuitry in the brain as options to prevent/control addiction, but outcomes and long-term effects are not known yet. In addition, novel treatments targeting cannabinoid receptors (neutral CB1R antagonists (such as AM4113), CB2R agonists (JWH133, Xie2–64), and nonselective phytocannabinoids (cannabidiol, β-caryophyllene, Δ9-tetrahydrocannabivarin) show promise. Cannabinoid-based medications (e.g., dronabinol, nabilone, PF-04457845) that entered clinical trials have shown promising results in reducing withdrawal symptoms in cannabis and opioid users.[128] Another future promising area of research in the search for drugs with less opioid abuse liability are ligands targeting the delta/kappa opioid receptors.[129, 130] A novel research area in modifiable factors is epigenetics – there has been research targeting BET (bromodomains and extra-terminal) subfamily inhibitors which read acetylated-lysine residues on chromatin[131], but clearly more research is needed in molecular genetics for development if new medication strategies to fight opioid addiction[132]. An out-of-the box approach is the development of anti-opioid vaccines.[132, 133] Only future trials will determine if these approaches will be effective. Last but not least, the psychology of addiction underlines the promise of neurobehavioral approaches especially in the vulnerable adolescent period.[134]

Article highlights.

• Opioid abuse is a multifactorial disorder that is associated with disrupted sub-cortical reward circuits and decision-making abilities.

• This review characterizes the PK-PD of opioids commonly used in abuse, and describes implications for abuse liability and development of opioid abuse deterrent formulations.

• Parameters such as drug physicochemical properties, C_max, T_max, rate/route of administration, absorption rate, receptor affinity, on-off kinetics and development of tolerance to opioid effects play a role in abuse liability.

• There are six mechanisms that have been exploited to develop abuse deterrent opioids. However, these strategies are currently not cost-effective.