In the central nervous system (CNS), excitatory neurons fire regularly, and inhibitory neurons inhibit the transmission of these impulses. Whenever action is required, the inhibitory tone diminishes, permitting the excitatory nerve impulses to travel to their end organs. Thus, all action in human neurophysiology can be considered to result from disinhibition.

Tonic inhibition (sustained, as opposed to phasic or transient inhibition) triggered by the constant presence of a xenobiotic produces an adaptive change in the affected neuron such that the constant presence of that xenobiotic is required to prevent dysfunction. A withdrawal syndrome occurs when the constant presence of this xenobiotic is removed or reduced and the adaptive changes persist. Withdrawal is a dysfunctional condition in which tonic inhibitory neurotransmission is significantly reduced, essentially producing excitation (Fig. 14–1). Every withdrawal syndrome has 2 characteristics: (1) a preexisting compensatory physiologic adaptation to the continuous presence of a xenobiotic and (2) decreasing concentrations of that xenobiotic below some threshold necessary to prevent physiologic derangement. In contrast, simple tolerance to a xenobiotic is characterized by a shift in the dose–response curve to the right; that is, greater amounts of a xenobiotic are required to achieve a given effect. Physiologic dependence, commonly referred to as dependence, occurs when the absence of the xenobiotic leads to the development of a specific withdrawal syndrome. Dependence needs to be distinguished from addiction, which is compulsive drug-seeking behavior. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), uses the term substance use to combine the DSM-IV disorders of substance abuse and substance dependence.¹

Withdrawal is manifested by either of the following: (1) a characteristic withdrawal syndrome for the xenobiotic, or (2) the same (or a closely related) xenobiotic is taken to relieve withdrawal symptoms. Note that either criterion fulfills this definition. Logically, all syndromes meet the first criterion, so it is the presence of the second criterion that is critical to understanding physiology and therapy.

For the purposes of defining a unifying pathophysiologic pattern of withdrawal syndromes, this chapter considers syndromes in which both features are present. An analysis from this perspective distinguishes xenobiotics that affect the inhibitory neuronal pathways from those that affect the excitatory neuronal pathways, such as cocaine. According to this definition, cocaine does not produce a withdrawal syndrome but rather a posttoxicity syndrome that often results in lethargy, hypersomnolence, movement disorders, and irritability. Although referred to as withdrawal, this syndrome does not meet the definition for a withdrawal syndrome because the same (or a closely related) xenobiotic is not taken to relieve or avoid withdrawal symptoms. This posttoxicity syndrome, the so-called “crack crash” or “washed-out syndrome,” is caused by prolonged use of cocaine, and patients ultimately return to their premorbid function without intervention. This distinction is important for toxicologists, because (1) withdrawal syndromes that demonstrate both features of the DSM-5 criteria are treated with reinstatement and gradual withdrawal of a xenobiotic that has an effect on the receptor and (2) withdrawal syndromes that do not demonstrate the second feature require only supportive care and resolve spontaneously. The term “drug discontinuation syndrome” is used instead of withdrawal, for example, with serotonin reuptake inhibitors to describe the symptoms that result when a drug used therapeutically is discontinued, but this is in fact a withdrawal syndrome. Addiction and dependence are terms often used in the context of the psychosocial aspects of xenobiotic use and are meant to convey the continued use of a xenobiotic despite adverse consequences.

Finally, withdrawal syndromes are best described and treated according to the class of receptors primarily affected because this concept also organizes the approach to patient care. For each receptor and its agonists, research has identified genomic and nongenomic effects that produce neuroadaptation and withdrawal syndromes. Six mechanisms appear to be involved: (1) epigenetic mechanisms via micro-RNA (miRNA) and messenger RNA (mRNA) expression, DNA methylation, and histone modification; (2) second-messenger effects via protein kinases, cyclic adenosine monophosphate (cAMP),^44,48 or calcium ions; (3) receptor endocytosis; (4) expression of various receptor and neurotransmitter transporter subtypes depending on location within the synapse (synaptic localization); (5) intracellular signaling via effects on other receptors; and (6) neurosteroid modulation. Some or all of these mechanisms are demonstrated in each of the known withdrawal syndromes.^52,53 These mechanisms develop in a surprisingly rapid fashion and modify the receptor and its function in such complex ways as to depend on the continued presence of the xenobiotic to prevent dysfunction.^{50,59,72,80,81}

γ-Aminobutyric acid type A (GABA_A) receptors are part of a superfamily of ligand-gated ion channels, including nicotinic acetylcholine receptors and glycine receptors, which exist as pentamers arranged around a central ion channel. When activated, they hyperpolarize the postsynaptic neuron by facilitating an inward chloride current (without a G protein messenger), decreasing the likelihood of the neuron firing an action potential. γ-Aminobutyric acid type A (GABA_A) receptors have separate binding sites for GABA, barbiturates, benzodiazepines, loreclezole, and picrotoxin (Chap. 13).⁶⁵ Barbiturates and benzodiazepines bind to separate receptor sites and enhance the affinity for GABA_A at its receptor site.

The GABA receptor is a pentamer composed of 2 α subunits, 2 β subunits, and 1 additional subunit, most commonly γ, which is a key element in the benzodiazepine-binding site. Each receptor has 2 GABA-binding sites that are located in a homologous position to the benzodiazepine site between the α and β subunits. Although the mechanism is unclear, benzodiazepines have no direct functional effect without the presence of GABA. Conversely, certain barbiturates in a dose-dependent manner and propofol can directly increase the duration of channel opening, thereby producing a net increase in current flow without GABA binding. This process has therapeutic implications and explains why high-dose barbiturates are nearly universally successful in stopping status epilepticus and treating severe withdrawal.

This prototypical pentameric GABA_A receptor assembly is derived from permutations and combinations of 2, 3, 4, or even 5 different protein subunits. The subtypes of GABA receptors can even vary on the same cell. In fact, GABA receptors are heterogeneous receptors with different subunits and distinct regional distribution. Although the preponderance of subtypes α₁β₂γ₂, α₂β₃γ₂, and α₃β₃γ₂ accounts for 75% of GABA receptors, there are at least 16 other significant subtypes.⁸¹ The recognition of additional subunits of GABA_A receptors facilitated the development of targeted pharmaceuticals, such as zolpidem.¹⁰

Previously, ethanol was thought to have GABA receptor activity, although a clearly identified binding site was not evident. Traditional explanations for this effect included (1) enhanced membrane fluidity and allosteric potentiation (so-called cross-coupling) of the 5 proteins that construct the GABA_A receptor; (2) interaction with a portion of the receptor; and/or (3) enhanced GABA release. Research with chimeric reconstruction of GABA_A and N-methyl-D-aspartate (NMDA) channels demonstrates highly specific binding sites for high doses of ethanol that enhance GABA_A and inhibit NMDA receptor-mediated glutamate neurotransmission. However, research has not clarified whether ethanol at low concentrations is a direct agonist of GABA_A receptors or a potentiator of GABA_A receptor binding.⁶⁶

There are 6 mechanisms of adaptation to chronic ethanol exposure making it the prototypical xenobiotic for the study of neuroadaptation and withdrawal.^25,52,58 These 6 mechanisms appear to apply to benzodiazepines as well.^4,66 The 6 mechanisms are (1) altered GABA_A receptor gene expression via alterations in miRNA, mRNA, and protein concentrations of GABA_A receptor subunits in numerous regions of the brain (genomic mechanisms); (2) posttranslational modification through phosphorylation of receptor subunits with protein kinase C (second-messenger effects); (3) subcellular localization by an increased internalization of GABA_A receptor α₁-subunit receptors (receptor endocytosis); (4) modification of GABA and NMDA receptor subtypes with differing affinities for agonists to the synaptic or nonsynaptic sites (synaptic localization) reducing the sensitivity of the receptor; (5) regulation via intracellular signaling by the NMDA, acetylcholine, serotonin, and β-adrenergic receptors; and (6) neurosteroidal modulation of GABA receptor sensitivity and expression.^20,21,44,54 Furthermore, changes in GABA_A subunit composition and function are evident within one hour of administration of a single exposure to ethanol in animals.⁵⁷

Intracellular signaling via the NMDA subtype of the glutamate receptor appears to explain the “kindling” hypothesis, in which successive withdrawal events become progressively more severe.^17,58 The activity of excitatory neurotransmission increases the more it fires, a phenomenon known as long-term potentiation, and is the result of increased activity of mRNA and receptor protein expression, a genomic effect of intracellular signaling.⁷⁷ As NMDA and other glutamatergic receptors (kainite and α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid {AMPA}) increase in number and function (upregulation) and GABA_A receptor activity diminishes, withdrawal becomes more severe.^42,58,75 The dizocilpine (MK-801)-binding site of the NMDA receptor appears to be the major contributor, and this effect is recognized in neurons that express both NMDA and GABA_A receptors.⁵ When the concentration of ethanol or any xenobiotic with GABA agonist activity is diminished, inhibitory control of excitatory neurotransmission, such as that mediated by the now upregulated NMDA receptors, is lost.⁵⁹ Additionally, increased presynaptic glutamate release is noted in withdrawal.²⁷ These effects result in the clinical syndrome of withdrawal: CNS excitation (tremor, hallucinations, seizures) and autonomic stimulation (tachycardia, hypertension, hyperthermia, diaphoresis) (Chap. 77).⁷²

Volatile solvents, such as gasoline, diethyl ether, and toluene, are widely abused xenobiotics whose effects also appear to be mediated by the GABA receptor (Chap. 81).^70,74 These solvents produce CNS inhibition and anesthesia at escalating doses via the GABA_A receptor in a fashion similar to that of ethanol.^16,47,83

In addition to GABA receptor/neurotransmitter effects, other neurotransmitters are important in the development of ethanol tolerance and withdrawal. These include an NMDA receptor subunit and anchoring protein, the dynorphin/kappa opioid receptor, the 5-HT_2C serotonergic receptors, serum nerve growth protein, and brain voltage-gated calcium channels.^34,60 Ethanol use is also associated with increased expression of pronociceptin and increased activity in the dynorphin/kappa opioid receptor system causing an altered affective condition.^22,31 Symptoms of ethanol withdrawal correlate with increased synthesis of mRNA for the nociceptin/orphanin FQ (N/OFQ)-opioid peptide receptor, which are involved in CNS stress-regulatory systems.¹¹ Once withdrawal has started, increases are noted in serum nerve growth protein, which is theorized to counteract excitatory states, and decreases in methylation of the gene coding for its transcription.⁴³ Finally, electrical current through brain voltage-gated calcium channels is increased in those chronically exposed to ethanol, and increased Ca²⁺ conduction may play a role in ethanol withdrawal seizures.⁶²

GABA_B agonists such as γ-hydroxybutyric (GHB) acid, γ-hydroxybutyrate (GHB) precursors and analogs, and baclofen have similar clinical characteristics with regard to adaptation and withdrawal.⁸⁴ The GABA_B receptor is a heterodimer of the GABA_B1 and GABA_B2 receptors. Unlike GABA_A, the GABA_B receptor couples to various effector systems through a signal-transducing G protein.^24,84 GABA_B receptors mediate presynaptic inhibition (by preventing Ca²⁺ influx) and postsynaptic inhibition (by increasing K⁺ efflux). The postsynaptic receptors appear to have an inhibitory effect similar to that of the GABA_A receptors, though the mechanism differs. The presynaptic receptors provide feedback inhibition of GABA release.

γ-Hydroxybutyric acid is a naturally occurring inhibitory neurotransmitter with its own distinct receptor (Chap. 80).⁷ Physiologic concentrations of GHB activate at least 2 subtypes of a distinct GHB receptor (antagonist-sensitive and antagonist-insensitive). However, at supraphysiologic concentrations, such as those that occur after overdose and abuse, GHB binds directly to the GABA_B receptor and is metabolized to GABA (which then activates the GABA_B receptor). The GHB withdrawal syndrome clinically resembles the withdrawal syndrome from ethanol and benzodiazepines and can be severe. In most cases, distinctive clinical features of GHB withdrawal are relatively mild with brief autonomic instability and the persistence of psychotic symptoms.⁷⁹

Baclofen is also a GABA_B agonist. The presynaptic and postsynaptic inhibitory properties of baclofen allow it, paradoxically, to cause seizures associated with both acute overdose because of decreased release of presynaptic GABA via autoreceptor stimulation and withdrawal. Withdrawal is probably a result of the loss of the chronic inhibitory effect of baclofen on postsynaptic GABA_B receptors. Discontinuation of baclofen produces hyperactivity of neuronal Ca²⁺ channels (N, P/Q type),³² leading to seizures, hypertension, hallucinations, psychosis, and coma. However, many of these manifestations do not differ clinically from the withdrawal symptoms of GABA_A agonists.

Typically, the development of a baclofen withdrawal occurs 24 to 48 hours after discontinuation or a reduction in the dose of baclofen. Case reports highlight the development of seizures, hallucinations, psychosis, dyskinesias, and visual disturbances. Additionally, the intrathecal baclofen pump is an effective replacement for oral dosing, but severe withdrawal can occur when the pump malfunctions or becomes disconnected.¹² Reinstatement of the prior baclofen-dosing schedule appears to resolve these symptoms within 24 to 48 hours. Benzodiazepines and GABA_A agonists are the appropriate treatment for seizures induced by baclofen withdrawal.⁷³