Treatment of Neonatal Abstinence Syndrome: History
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Contributor:
Mauro Ceccanti
,
Kenneth Blum
,
Abdalla Bowirrat
,
Catherine A. Dennen
,
Eric R. Braverman
,
David Baron
,
Thomas Mclaughlin
,
John Giordano
,
Ashim Gupta
,
Bernard W. Downs
,
Debasis Bagchi
,
Debmalya Barh
,
Igor Elman
,
Panayotis K. Thanos
,
Rajendra D. Badgaiyan
,
Drew Edwards
,
Mark S. Gold

The management of neonatal abstinence syndrome (NAS) is varied and involves a combination of nonpharmacologic and pharmacologic therapy. The treatment goals for NAS include preventing NAS-associated complications and restoring normal newborn activities, such as nutrition intake, weight gain, sleep, and adjustment to the social environment. As with all pharmacological treatments, the potential risks and benefits of treatment must be considered for each patient.

  • neonatal abstinence syndrome (NAS)
  • reward deficiency syndrome (RDS)
  • genetic addiction risk severity (GARS)

1. Nonpharmacological Interventions

Nonpharmacologic care should be initiated at birth for all substance-exposed newborns, and the parent/caregiver should also be actively involved. It should continue throughout the newborn’s hospitalization and after discharge, regardless of the need for pharmacologic treatment. When used appropriately, nonpharmacologic therapies can help newborns with neonatal abstinence syndrome (NAS) avoid or reduce the amount of pharmacologic therapy required. However, they do not serve as a substitute for pharmacotherapy when it is necessary. Nonpharmacologic therapies entail individualized assessments of the newborn and parent/caregiver’s functioning; the environment, to determine specific newborn–parent/caregiver dyad triggers for dysregulation; and adaptative responses to the environment to reduce physiological and neurobehavioral symptoms and promote newborn–parent/caregiver dyadic regulation [1].
General care measures [1][2]:
General care measures in NAS include identifying the signs, symptoms, and triggers of physiological behavioral dysregulation and individualizing the care of the newborn based on these observations as well as promoting organization, competence, and physiological stability in newborns by identifying techniques that improve symptomatology that are specific to each newborn. For example, gentle vertical rocking can help reduce excessive irritability. Moreover, tremors and hypertonicity can be reduced by utilizing swaddling and positioning (i.e., the side-lying C position), which decrease motoric hyperactivity and allow newborns to organize their behaviors and become calm.
Newborn–parent/caregiver relationship [1]:
Nonpharmacologic interventions in this domain include assessing parental functioning and interaction with the newborn to help reduce dysregulation and promote dyadic synchronization [3]; educating the parent/caregiver on how to identify the signs of withdrawal; teaching the parent/caregiver about their newborn’s sensitivities; helping the parent/caregiver develop strategies and respond to the newborn in a manner that reduces the newborn’s dysregulation and expression of NAS; aiding the parent/caregiver in understanding their feelings surrounding their newborn’s functioning so they can respond more appropriately; and managing maternal issues such as mental illness, limited health care access, intimate partner violence, etc., in order to maintain a healthy newborn–parent/caregiver relationship, which is vital for the newborn’s development [4].
Environment [2]:
Nonpharmacologic interventions in this domain include identifying potential sensory and environmental input sources of dysregulation for newborns and altering the environment to minimize their effects and dysregulation. For example, a newborn who becomes hypertonic or irritable with eye contact might need the parent/caregiver to avoid eye contact while feeding, handling, or performing other activities together. In addition, a newborn who becomes easily overstimulated by noise can be cared for in a quiet area. Finally, rooming-in (i.e., the colocation of the newborn and the parent/caregiver after delivery and beyond) has been found to reduce NAS severity [2][5][6] and is recommended in the inpatient setting.
Feeding:
For newborns with NAS, formula feeding should not necessarily be the default. In fact, breastfeeding has been shown to be successful in some individuals with opioid use disorder (OUD) [2][7][8][9]. Recommendations involving an individual’s suitability for breastfeeding should be tailored for individuals with one or more of the following traits: the concurrent usage of other prescription medications; participation in prenatal care and/or substance use disorder (SUD) treatment during or after the second trimester; and relapse during the third trimester with abstinence maintained for 30 days prior to delivery.
Breastfeeding by methadone-maintained individuals seems to be safe and can lessen the severity of NAS and the necessity for pharmacological intervention [10][11][12][13]. The concentrations of methadone have been found to be low in human breast milk (range: 21–462 ng/mL) and do not appear to be associated with the parent’s methadone dose [10]. The low concentrations of methadone found in human breast milk are unlikely to have a significant impact on the newborn’s display of NAS, and other breastfeeding-related variables could be responsible for the decreased severity of NAS in breastfed infants of methadone-maintained individuals. In addition, buprenorphine is excreted in low concentrations into human breast milk and seems to be safe for newborns of buprenorphine-maintained individuals [14][15].

2. Pharmacological Interventions

Pharmacological management is initiated for newborns who display significant signs and symptoms of NAS despite adequate and personalized nonpharmacological care. The goal of pharmacological management is a short-term improvement in NAS symptomatology. Currently, opioid therapy is the preferred first-line treatment for NAS. This is based on limited data that show opioid therapy reduces the need for additional medications and shortens hospital stays [2][4][16][17][18][19]. Morphine and methadone are the preferred opioids, and the selection is based on the clinician/hospital. Morphine is typically the preferred agent of the two, while methadone is considered a reasonable alternative. However, there have been studies that indicate that methadone minimally reduces hospital stay and treatment duration when compared to morphine [20][21]. Buprenorphine is another agent that has been used and appears to be effective in the treatment of NAS [22][23]. However, its use in newborns is limited due to the high ethanol content (30%) and its challenging sublingual administration [2].
A 2020 systematic review by Zankl et al. identified 16 trials including 1110 infants [4]. In one of the trials (N = 80 infants), morphine was compared to supportive care alone, and the results showed that morphine increased the length of treatment and hospitalization but shortened the time needed to regain birthweight. In trials that compared morphine to methadone (two trials, N = 147 infants), it was found that they both had comparable rates of breastfeeding success, length of hospitalization, and treatment failure. In trials that compared morphine to buprenorphine (three trials, N = 113 infants), it was found that they both had comparable rates of treatment failure, but the length of hospitalization was shorter in the buprenorphine group. In a separate network meta-analysis utilizing both indirect and direct comparisons (18 trials, N = 1072 infants), six medications were evaluated, including morphine, methadone, buprenorphine, clonidine, phenobarbital, and DTO. Morphine and methadone were associated with the lowest rates of treatment failure, but the differences were not statistically significant [24]. Additionally, buprenorphine was found to have the shortest length of hospitalization.
In addition, according to a meta-analysis by Cleary et al., there were no statistically significant differences in the incidence of NAS in newborns of women on higher doses of opioids when compared to lower doses in studies that used an objective NAS scoring system and prospective studies [25]. Similarly, Bakstad et al. reported that the maternal methadone or buprenorphine dose was not predictive of the occurrence or need for NAS treatment in newborns [26].
A second medication is sometimes required in newborns who have severe NAS that is not sufficiently controlled with a single agent [4][24][27][28]. The two most commonly used second-line medications are clonidine and phenobarbital. Typically, clonidine is the preferred second-line medication due to concerns regarding phenobarbital’s adverse effects, including oversedation, a high alcohol content, challenges with weaning substance-exposed newborns from phenobarbital, and phenobarbital’s potential long-term impacts on neurodevelopment based on animal studies [2][29][30][31][32]. In addition, the concurrent use of phenobarbital and clonidine appears to reduce the consequences of opioid-induced negative neuronal development in newborns with NAS [27][33].

3. Neurodevelopmental Issues with Opioid Treatment

Czynski et al. [34] reported that the prevalence of NAS has increased by 333% over the last two decades, which translates to approximately one infant born every 15 min in the United States [35]. This unfortunate statistic reveals that 50–80% of newborn infants exposed to opioids in utero develop NAS. Along these lines, Boardman et al. [36] suggested that a literature summary of 40 years necessitated a reassessment of ways to treat NAS without opioids, even during withdrawal periods. These investigators identified knowledge gaps and urged the scientific community to re-evaluate childhood clinical outcomes such as infant brain development and visual and long-term neurocognitive function. Van den Hoogen et al. [37], assessing the behavioral and cFos responses, known to be a marker for neuronal activation in neonatal animals withdrawing from opioids, found increased cFos expression in spinally projecting neurons within the periaqueductal grey (PAG), locus coeruleus, and rostral ventromedial medulla (RVM). They also observed that the narcotic antagonist naloxone precipitated profound withdrawal symptoms across all developmental levels and stages within several key brainstem regions. Another example of neurodevelopmental issues linked to opioids was investigated by others [34], involving mothers maintained on methadone or buprenorphine but randomized to morphine vs. methadone. Czynski et al. [34] reported that adding phenobarbital to the treatment routine resulted in several medical problems, suggesting that sedative hypnotics may not be an appropriate modality in these NAS cases. Finally, Witt et al. [38] evaluated long-term childhood and infant mortality involving 1900 individuals diagnosed with NAS and 12,283 controls. The results indicated that NAS-diagnosed children were readmitted to the hospital within five years of life more frequently when compared to non-NAS controls. Most perplexing was the finding that in NAS patients there was an unadjusted significant increased mortality risk ratio of 1.94 (95% CI 0.99–3.80). Witt and associates [38] concluded that childhood readmission due to NAS “argues” for innovative (possibly nonpharmacological) early interventions to prevent morbidity and possibly mortality.

4. A Case in Favor of Non-Opioid Treatment in NAS

Opioid pharmacokinetics are influenced in neonates by a higher body water content that can alter drug distribution and metabolic processes that are not mature and can lead to low plasma protein and liver enzyme activity. For example, these factors could affect cleared metabolites, resulting in a prolonged half-life of opioids. This is further complicated by reduced renal excretion, which might be due to immature tubular secretion, glomerular filtration, and reabsorption [39]. In addition, animal experiments have shown that an immature blood–brain barrier in neonates may result in an augmented sensitivity to opioids [40].
An argument against the utilization of opioids to treat NAS has been espoused by some investigators globally [41][42][43][44], and a word search for “acupuncture and NAS” revealed 102 PubMed listings (26 January 2022). Following an extensive review of the literature, including the Cochrane Databases, Jackson et al. [41] reported that acupuncture is a safe and effective nonpharmacological alternative to potent opioids for the treatment of NAS.
If further confirmed in more extensive studies, using nutraceutical complex prodopaminergic regulator (KB220Z) for opiate/opioid detoxification may provide a novel way to eliminate the need for addictive opioids during withdrawal and detoxification. This paradigm shift, which requires extensive research, may translate to a reduction in universally employing powerful and addictive opioids to treat OUD and NAS [45].

5. Snapshot of Dopaminergic Mechanisms in Addiction

As Poisson et al. [46] pointed out, most of the brain’s dopamine neurons are in two midbrain regions: the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc). Others revealed that DA neurons in the VTA mainly project to the ventral striatum, specifically the nucleus accumbens (NAc) core and shell. The NAc shell comprises the mesostriatal pathway and links to certain frontal regions in the prefrontal cortex, pallidum, and amygdala [47][48]. The work of Nestler’s group [49] and others [50][51] has shown that DA neurons in the VTA intermingle with GABAergic (gamma-aminobutyric acid (GABA)) and glutamatergic neurons. In contrast, the SNc DA neurons project to the dorsomedial (DMS) and dorsolateral (DLS) striatum almost exclusively and comprise a well-known nigrostriatal system [52][53][54]. Importantly, in the striatum, Gerfen [55] showed that DA neurons contact GABAergic medium spiny neurons (MSNs) that contain excitatory type 1 (D1-MSNs) or inhibitory type 2 (D2-MSNs) DA receptors. Kupchik et al. [56] have further confirmed this work. The primary role of DA’s modulatory effect on striatal activity due to these outputs involves the control of specific behaviors (such as motivation and reward learning). It is indeed well known that most highly addictive psychoactive drugs (such as cocaine, alcohol, and morphine) cause the release of DA in the NAc and other striatal regions. According to Collins and Saunders [57], based on terminal mechanisms, DA release may play an essential role in many infractions related to aberrant drug use and cravings and even drug reinstatement or relapse, the cornerstone of unwanted SUD [58][59][60][61][62]. A review of the literature revealed that DA neurons across the VTA and SNc circuitry impact a wide array of behavioral functions, showing significant overlap or co-occurrence across many reward-related behaviors [63][64][65][66]. Mesostriatal DA neurons contribute to the execution of goal-directed behaviors and learning. However, nigrostriatal DA, specifically in the DLS, impacts movement control and even the execution of rigid habitual actions that translate to addiction heterogeneity [67][68][69][70][71][72]. It is important to recognize that DA has a powerful effect on many behaviors that, when impaired, induce in the reward circuitry maladapted dysfunctional behaviors and addiction, including poor decision making, a prominent underpinning of compulsive behaviors [73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104].

6. Evidence-Based Prodopaminergic Regulation (KB220)

Genetic polymorphisms of the catechol-o-methyltransferase (COMT) and mu-opioid receptor (OPRM1) genes appear to affect the length of stay and the need for pharmacotherapy in newborns with prenatal opioid exposure [105]. These findings are consistent with data from adult studies that demonstrated that variations in these genes are associated with adult opioid dependence variability [106]. Epigenetic modifications to the OPRM1 gene have also been linked to the severity of NAS [107]. Thus, it appears prudent to incorporate genetic testing in order to reveal reward circuitry gene polymorphisms, especially those associated with dopaminergic pathways and opioid receptors, as a means of improving NAS treatment outcomes [108].
In the most recent reiteration, additional nutrients have been added to the formula, such as β-nicotinamide adenine dinucleotide (β-NAD) to function as a catalyst for dopamine synthesis [109] and N-acetyl-cysteine [110] to help promote glutaminergic drive in the VTA to release DA in the NAc.
The neurological effects of precision amino-acid enkephalinase inhibition therapy (KB220)  in naïve rodents, uncovered in studies conducted by Marcelo Febo [111], showed blood oxygen level dependent (BOLD) activation using KB220 in regions of interest related to the brain reward circuitry. Specifically, there was a significant increase in the functional connectivity of the NAc with the medial and lateral anterior thalamic nucleus and the surrounding somatosensory cortex. Another important finding revealed that KB220Z augmented the connectivity between corticothalamic areas and this region of the reward system.
Additionally, with KB220Z vs. placebo, when the anterior thalamic nucleus was the selected seed RIO, there was minimal evidence of connectivity observed outside this area. Febo et al. [111] found a significant enhancement in connectivity with surrounding sensory cortical areas and the regions mentioned above, including the NAc (both left and right). A more substantial effect on the resting state functional connectivity (rsFC) in the dorsal hippocampus was of real interest. Furthermore, connectivity was increased between the left and right dorsal hippocampi, the upper limb somatosensory regions, the NAc and limbic cortical areas, and the anterior cingulate.
A follow-up study utilizing KB220Z was also administered to abstinent Chinese heroin abusers to help map the brain reward circuitry interaction potential in humans. Along these lines, it is noteworthy that Willuhn et al. [112] reported that cocaine use and even non-substance-related addictive behavior surge as dopaminergic function is decreased. Understanding that reduced or deficient levels of brain DA enhance heroin-seeking behavior. Treatment strategies, including a DA agonist therapy that conserves dopamine function, could prevent relapse to opioids.
The effect of KB220Z on the reward circuitry of ten heroin addicts undergoing protracted abstinence for an average of 16.9 months was investigated [113]. Specifically, in a randomized, placebo-controlled crossover study of KB220Z, five subjects completed the triple-blinded experiment. Additionally, nine patients were genotyped utilizing the genetic addiction risk severity (GARS) test.
KB220Z induced an enhanced BOLD activation in caudate–accumbens–dopaminergic pathways compared to placebo following a one-hour acute administration. Moreover, KB220Z also attenuated the resting state activity in the putamen of abstinent heroin-dependent subjects. In the second phase of this preliminary investigation of all ten abstinent heroin-dependent patients, three brain regions of interest were significantly activated from the resting state by KB220Z compared to placebo.
Interestingly, augmented functional connectivity was observed in a putative network that included the cerebellum, medial frontal gyrus, dorsal anterior cingulate, NAc, occipital cortical area, and posterior cingulate. These results and other qEEG studies [114][115] support the notion of a putative anticraving/anti-relapse role for KB220Z in opioid dependence by direct or indirect dopaminergic interaction.
Preclinical experiments and human trials associated with KB220 variants have been published and reviewed [116]. Early formulations of KB220 increased brain enkephalin levels in rodents [112], reduced alcohol-seeking behavior in C57/BL mice [113], and converted ethanol-preferring C57/BL mice via pharmacogenetics to the same level of nonpreference as alcohol-averse DBA mice [112]. Thus, based on these and other animal and human studies [114][115][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145][146][147], using KB220Z might be an ideal treatment for NAS, particularly to counteract underlying brain hypodopaminergia.

7. Common Neurochemical Mechanisms Related to Alcohol and Opiate/Opioid-Induced Withdrawal Symptomatology

Wallace et al. [148] reported that as many as 47% of pregnant women misuse/abuse alcohol, and at least 6% misuse or abuse illegal drugs such as opioids. The European Monitoring Centre for Drugs and Drug Addiction has noted that approximately 500 thousand opioid-dependent Europeans are, unfortunately, on opioid maintenance substitution therapy (OMST) [149]. It is indeed a fact that about 30,000 opioid-dependent women have become pregnant [150]. The treatment of women involved with a combination of alcohol and opioid dependence is very complex and is a challenge that must be faced to attenuate the onslaught of unwanted NAS [151][152].
Since the early 1970s, Blum’s group has investigated the common neurochemical and genetic underpinnings of all addictive behaviors. One area of investigation by this group was a common mechanism among opiates, alcohol, and neurotransmitter involvement in withdrawal symptomology—the commonality concept related to condensation products derived from the identification of in vivo isoquinoline formation. There is enough evidence to suggest that these condensation amines “link” to opiates. The message here is that when one imbibes alcohol, opiate-like isoquinolines are formed [153]. These isoquinolines induce a robust enhancement of ethanol-induced withdrawal symptoms (EIW) [154]. For example, a series of experiments revealed that the inhibition of catecholamine synthesis results in the potentiation of EIW [155]; haloperidol, a D2 dopamine receptor (DRD2), potentiates EIW [156]; serotonergic blockers potentiate EIW [157]; dopamine suppresses EIW [158]; morphine suppresses EIW [159][160]; naloxone inhibits alcohol dependence [161]; and clonidine enhances EIW [162][163][164].
Of interest is the finding that by employing quantitative electroencephalography (qEEG) as an imaging tool, Miller et al. [131] showed the impact of one formulation of KB220 as a putative activator of the mesolimbic system. These investigators [131] found that intravenous administration reduces or “normalizes” aberrant electrophysiological parameters of the brain reward circuitry region. Specifically, KB220 significantly normalized widespread theta and alpha activity in alcoholics and heroin abusers, showing several neurotransmitter-linked polymorphic genes measured by the GARS test. The authors [131] suggested that the chronic activation of dopaminergic receptors, such as DRD2, will increase upregulation, induce an augmented “dopamine sensitivity,” and ultimately “enhance the sense of happiness,” specifically, for example, in carriers of the DRD2 A1 allele.

This entry is adapted from the peer-reviewed paper 10.3390/jpm12122015

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  153. Blum, K.; Hamilton, M.G.; Hirst, M.; Wallace, J.E. Putative Role of Isoquinoline Alkaloids in Alcoholism: A Link to Opiates. Alcohol. Clin. Exp. Res. 1978, 2, 113–120.
  154. Blum, K.; Eubanks, J.D.; Wallace, J.E.; Schwertner, H.; Morgan, W.W. Possible role of tetrahydroisoquinoline alkaloids in post alcohol intoxication states. Ann. N. Y. Acad. Sci. 1976, 273, 234–246.
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  156. Blum, K.; Eubanks, J.D.; Wallace, J.E.; Hamilton, H. Enhancement of Alcohol Withdrawal Convulsions in Mice by Haloperidol. Clin. Toxicol. 1976, 9, 427–434.
  157. Blum, K.; Wallace, J.E.; Schwertner, H.A.; Eubanks, J.D. Enhancement of ethanol-induced withdrawal convulsions by blockade of 5-hydroxytryptamine receptors. J. Pharm. Pharmacol. 1976, 28, 832–835.
  158. Blum, K.; Eubanks, J.D.; Wallace, J.E.; Schwertner, H.A. Suppression of ethanol withdrawal by dopamine. Experientia 1976, 32, 493–495.
  159. Blum, K.; Wallace, J.E.; Schwerter, H.A.; Eubanks, J.D. Morphine suppression of ethanol withdrawal in mice. Experientia 1976, 32, 79–82.
  160. Blum, K.; Baron, D.; McLaughlin, T.; Gold, M.S. Molecular neurological correlates of endorphinergic/dopaminergic mechanisms in reward circuitry linked to endorphinergic deficiency syndrome (EDS). J. Neurol. Sci. 2020, 411, 116733.
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  162. Blum, K.; Briggs, A.H.; DeLallo, L. Clonidine enhancement of ethanol withdrawal in mice. Subst. Alcohol Actions Misuse 1983, 4, 59–63.
  163. Roehrich, H.; Gold, M.S. Clonidine. Adv. Alcohol Subst. Abus. 1988, 7, 1–16.
  164. Gold, M.S.; Blum, K. Clonidine: The Locus Coeruleus & Noradrenergic Hyperactivity Theory for Opioid and other Drug Withdrawal from 1977 to Present. In Clonidine; Oxford Press: Oxford, UK, 2021.
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