15: Withdrawal Principles

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. 15–1). Every withdrawal syndrome has two characteristics: (1) a preexisting physiologic adaptation to a xenobiotic, the continuous presence of which prevents withdrawal, and (2) decreasing concentrations of that xenobiotic. In contrast, simple tolerance to a xenobiotic is characterized as a physiologic adaptation that shifts the dose–response curve to the right; that is, greater amounts of a xenobiotic are required to achieve a given effect. Physiologic dependence, generally simply called 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.³

Withdrawal is manifested by either of the following: (1) a characteristic withdrawal syndrome for the substance, or (2) the same (or a closely related) substance is taken to relieve withdrawal symptoms. Note that either criterion fulfills this definition. Logically, all syndromes have 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 postintoxication 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) substance is not taken to relieve or avoid withdrawal symptoms. This postintoxication 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-IV-TR 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 syndromes” has been used in particular 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) genomic mechanisms via mRNA, (2) second-messenger effects via protein kinases, cyclic adenosine monophosphate (cAMP),^17,19 or calcium ions, (3) receptor endocytosis, (4) expression of various receptor 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.^23,24 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.^{21,28,37,43,44}

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. 14).³¹ 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 comprised of two α subunits, two β subunits, and one additional subunit, most commonly γ, which is a key element in the benzodiazepine binding site. Each receptor has two 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 (perhaps all, 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 accounts for 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 two, three, four, or even five different 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 others of import.⁴⁴ The recognition of additional subunits of GABA_A receptors has permitted the development of targeted pharmaceuticals, such as zolpidem.⁵

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 five 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 doses is a direct agonist of GABA_A receptors or a potentiator of GABA_A receptor binding.³²

Ethanol exhibits six mechanisms of adaptation to chronic exposure and is the prototypical xenobiotic for studying neuroadaptation and withdrawal.^11,23,27 These six mechanisms appear to apply to benzodiazepines as well.^1,32 The mechanisms are (1) altered GABA_A receptor gene expression via alterations in mRNA and peptide 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 receptor subtypes with differing affinities for agonists to the synaptic or nonsynaptic sites (synaptic localization), (5) regulation via intracellular signaling by the NMDA, acetylcholine, serotonin, and β-adrenergic receptors, and (6) neurosteroidal modulation of GABA receptor sensitivity and expression.^9,17,25 Furthermore, changes in GABA_A subunit composition and function are evident within one hour of administration of a single dose of ethanol.²⁶

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.^7,27 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.⁴¹ As NMDA receptors increase in number and function (upregulation) and GABA_A receptor activity diminishes, withdrawal becomes more severe.^16,27,40 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.² When alcohol or any xenobiotic with GABA agonist activity is withdrawn, inhibitory control of excitatory neurotransmission, such as that mediated by the now upregulated NMDA receptors, is lost.²⁸ This loss results in the clinical syndrome of withdrawal: CNS excitation (tremor, hallucinations, seizures), and autonomic stimulation (tachycardia, hypertension, hyperthermia, diaphoresis) (Chap. 81).³⁷

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. 84).^35,39 These solvents can produce CNS inhibition and anesthesia at escalating doses via the GABA_A receptor in a fashion similar to that of ethanol.^6,18,46

GABA_B agonists such as γ-hydroxybutyric (GHB) acid, GHB precursors and analogs, and baclofen have similar clinical characteristics with regard to adaptation and withdrawal.⁴⁷ 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.^10,47 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.

GHB is a naturally occurring inhibitory neurotransmitter with its own distinct receptor (Chap. 83).⁴ Physiologic concentrations of GHB activate at least two 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 the relatively mild and brief autonomic instability and the persistence of psychotic symptoms.⁴²

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),¹² leading to seizures, hypertension, hallucinations, psychosis, and coma. However, these manifestations may 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 has become an effective replacement for oral dosing, but severe withdrawal can occur when the pump malfunctions or becomes disconnected. Reinstatement of the prior baclofen-dosing schedule appears to resolve these symptoms within 24 to 48 hours. Benzodiazepines and GABA_A agonists (not phenytoin) are the appropriate treatment for seizures induced by baclofen withdrawal.³⁸

Similar to the behavior of ethanol and GABA_A receptors, opioid binding to the opioid receptors results in a series of genomic and nongenomic neuroadaptations, especially via second-messenger effects. When opioids bind to opioid receptors they alleviate pain by inhibiting neurons, while activating G_s proteins and stimulating K⁺ efflux currents. The opioid receptors are also linked to the G_i/o proteins. They act through adenyl cyclase and inactivate inward Na⁺ current, thus suppressing the intrinsic excitability of a neuron (Chap. 38).

Chronic use of all xenobiotics with opioid-receptor affinity results in a decreased efficacy of the receptor to open potassium channels by genomic mechanisms and second-messenger effects. Following chronic opioid use, the expression of adenyl cyclase increases through activation of the transcription factor known as cAMP response element-binding protein (CREB) (Fig. 15–2).^15,29 This situation results in upregulation of cAMP-mediated responses such as the inward Na⁺ channels responsible for intrinsic excitability. The net effect is that only higher concentrations of opioids result in analgesia and other opioid effects. In the dependent patient, when opioid concentrations drop, inward Na⁺ flux occurs unchecked, and the patient experiences the opioid withdrawal syndrome. The clinical findings associated with this syndrome are largely a result of uninhibited activity at the locus ceruleus.^21,29

Furthermore, opioid receptors and central α₂-adrenergic receptors both exert an analogous effect on the potassium channel in the locus ceruleus. Clonidine binds to the central α₂-adrenergic receptor and stimulates potassium efflux, as do opioids, and produces similar clinical findings, which explains why clonidine has efficacy in treating certain aspects of the opioid withdrawal syndrome (cross tolerance). In addition, the antagonistic effect of naloxone at the opioid receptor seems to partially reverse the effect of clonidine on this shared potassium efflux channel.

Rapid and ultrarapid opioid detoxification are forms of intentional iatrogenic withdrawal that use opioid antagonists to accelerate a return to premorbid receptor physiology. In theory, although not necessarily in practice, inducing opioid withdrawal under general anesthesia with high-dose opioid antagonists permits the transition from drug dependency to naltrexone maintenance without enduring an intense withdrawal syndrome (Chap. 38).^13,14,20

In a manner related to their role in treating opioid withdrawal, prolonged exposure to clonidine and related medications are associated with a withdrawal syndrome. α₂-Adrenergic receptors are located in the central and peripheral nervous systems. Clonidine is a central and peripheral α₂-adrenergic agonist. Stimulation of central presynaptic α₂-adrenergic receptors inhibits sympathomimetic output and results in bradycardia and hypotension. Within 24 hours after the discontinuation of chronic clonidine use, norepinephrine concentrations rise as a result of enhanced efferent sympathetic activity. This increase results in hypertension, tachycardia, anxiety, diaphoresis, and hallucinations.

Dexmedetomidine is a medication that is gaining use as a sedative in the intensive care unit. Like clonidine it is a central and peripheral presynaptic α₂-adrenergic agonist, but dexmedetomidine has greater specificity for the α₂ receptor and hence stronger sedative properties. It cannot be given in bolus doses because it causes hypertension and tachycardia by stimulating peripheral α₂ receptors on vascular smooth muscle (much like the initial phase of a clonidine overdose).²² Dexmedetomidine has been used as an adjunct to treat alcohol, benzodiazepine, and opioid withdrawal and is reported to cause less respiratory depression than benzodiazepines but more bradycardia.³⁴ Importantly, dexmedetomidine has a withdrawal syndrome exactly like that of clonidine, including hypertension, tachycardia, and agitation. In fact, clonidine has been used to treat this withdrawal successfully.^36,45

The release of most neurotransmitters is accompanied by the passive release of adenosine as a byproduct of adenosine triphosphate (ATP) breakdown. The released adenosine binds to postsynaptic A₁ receptors where it typically has inhibitory effects on the postsynaptic neuron. It also binds to presynaptic A₁ autoreceptors to limit further release of neurotransmitters. A₂ receptors are found on the cerebral vasculature and peripheral vasculature where stimulation promotes vasodilation. Caffeine and other methylxanthines, such as theophylline, antagonize the inhibitory effect of adenosine, primarily on postsynaptic A₁ receptors. As a result, acute use results in increases in heart rate, ventilation, gastrointestinal motility, gastric acid secretion, and motor activity. Chronic caffeine use results in tolerance and the above symptoms diminish. Caffeine use upregulates A₁ receptors by a variety of mechanisms, including increases in receptor number, increases in receptor affinity, enhancement of receptor coupling to the G protein, and increases in G protein–stimulated adenyl cyclase. An animal study demonstrates that the adenosine receptor has a threefold increase in affinity for adenosine at the height of withdrawal symptoms. This model suggests that long-term caffeine administration results in an increase in receptor affinity for adenosine, thus restoring a state of physiologic balance (normal motor inhibitory tone). When caffeine is withdrawn, the enhanced receptor affinity results in a strong adenosine effect and clinical symptoms of withdrawal: headache (cerebral vasodilation), fatigue, and hypersomnia (motor inhibition).

A nicotinic receptor is a type of acetylcholine receptor located in the autonomic ganglia, adrenal medulla, CNS, spinal cord, neuromuscular junction, and carotid and aortic bodies. Nicotinic receptors are fast-response cation channels that are not coupled to G proteins, distinguishing them from muscarinic receptors, which are coupled to G proteins. Nicotinic acetylcholine receptors have both excitatory and inhibitory effects. As in other withdrawal syndromes, changes brought on by chronic use of nicotinic agonists, such as nicotine in cigarettes, appear to be related to selective upregulation of cAMP.^8,43

As mentioned above, drug discontinuation syndrome is a term used to describe the withdrawal syndrome associated with the therapeutic use of serotonin reuptake inhibitors. It meets the definition of withdrawal syndromes in that symptoms begin when xenobiotic concentrations drop, and the syndrome abates when the xenobiotic is reinstated.³⁰ Headache, nausea, fatigue, dizziness, and dysphoria are commonly described symptoms. The condition appears to be uncomfortable but not life threatening, rapidly resolves with reinstatement of a xenobiotic of the same class, and slowly resolves when the medication is discontinued after a more gradual taper (Chap. 75).³³

• Withdrawal occurs when a xenobiotic that has produced adaptive changes in a neuron is removed.

• The treatment of a withdrawal syndrome generally involves readministration of the xenobiotic from which the patient is withdrawing.

• In some situations, crosstolerant xenobiotics can be administered. Examples include the use of benzodiazepines and barbiturates to treat ethanol withdrawal or clonidine for opioid withdrawal.

References