The concept of anxiety as an emotional experience distinct from fear is a relatively modern notion with its origins in the works of Sigmund Freud. It is interesting historical trivia that the German word for fear, ‘angst’ was inappropriately translated in some of Freud’s work to the subtly different word, ‘anxiety.’¹ Although Freud made no distinction between fear and anxiety in his writings, this linguistic accident helped create a distinction between the concepts of fear and anxiety.¹ This distinction, especially in relation to chronic anxiety disorders, has held up to scientific scrutiny. Fear, broadly defined, is a complex emotional and physical response to an actual threat (i.e. response to a physical attack.) Anxiety, by contrast, is a complex emotional and physical response to a perceived threat (i.e. believing an attack is imminent). Both fear and its analog, anxiety, are responses to stress that, when functioning properly, are adaptive and necessary for survival. It is when the physical and emotional sequelae of fear and anxiety are excessive in relation to their context, or when they lead to a state of chronic incapacity and loss of function, that they become a cause for clinical concern. As outlined above, chronic pain creates many situations that may provoke fear or anxiety.

Acute fear in a perceived dangerous situation has the effect of modulating pain sensation to enable successful fight-or-flight reactions. In the patient with chronic pain, the role that fear and chronic anxiety has in the maintenance and exacerbation of their symptoms cannot be underestimated. The common physical symptoms of anxiety, such as muscular tension, hyperarousal, insomnia, palpitations, and poorly localized pain, often confound a patient’s primary medical or surgical pain complaint. Anxiety, through activation of the noradrenergic system in the locus coeruleus, has both peripheral and central effects on pain perception in persons with nociceptive, neuropathic and visceral pain conditions, as listed in Table 15.1. Add to this the psychological symptoms associated with anxiety (worry, apprehension, irritability, poor concentration, overinterpretation of symptoms) along with the effects of anxiety on illness behavior, including presentation of pain complaints and compliance with treatment regimens, and the complexity of treating a patient with chronic pain with acute or chronic anxiety becomes obvious.

Table 15.1 Effects of Anxiety on Pain Conditions and Disorders

Condition	Physiologic Effect of Anxiety	Consequences for Pain
Nociceptive pain	Sympathetic nervous system activation	Higher pain levels
	(1) lowering threshold for nociceptor activation

Increased sensitivity to pain stimuli

(2) activation of efferent motor neurons

Muscle spasm Neuropathic pain Sympathetic nervous system activation Acute activation of pain in response to stressful circumstances

(1) Activation of sodium channels in primary pain neurons and polymodal sensory neurons recruited to pain.

Increase in spontaneous neuronal firing with worsening pain

(2) Recruitment of inflammatory cells to injured neurons

Increase in spontaneous neuronal firing with worsening pain Visceral pain Sympathetic nervous system activation Stimulation of visceral plexuses with secondary pain effects such as activation of bowel in irritable bowel and bladder irritation in interstitial cystitis Central pain Activation of noradrenergic projections to brain centers of pain suffering and mood dyscontrol Reduced descending modulatory control of ascending pain signal. Conditioned activation of pain suffering Interference with task-oriented concentration Reduced distraction-based modulation of pain

Before moving to a discussion of the treatments for acute and chronic anxiety, it is necessary to briefly describe in more detail the neuroanatomical and biological correlates of fear, anxiety, and pain so we may better understand how they are interrelated.

THE BIOLOGICAL BASIS OF FEAR AND ANXIETY

The biological and anatomical substrates of fear as a trigger for a fight-or-flight response are ancient. Countless behavioral experiments have established that nearly every species, from snails to humans, can develop a conditioned fear response to noxious stimulus.

By contrast, chronic anxiety, because of its anticipatory nature, requires a greater degree of biological processing capacity. Humans, with a near infinite capacity to perceive and anticipate threat, are exquisitely equipped to experience anxiety.

Figure 15.1 is a conceptual rendition of the basic neuroanatomical components of fear. The connections between these structures are much more complex than the pathways depicted in this illustration, but they provide a general idea of how these anatomical structures communicate and synthesize environmental, emotional, and learned stimuli. The spatial relationship of the brain regions depicted in this illustration is generally analogous to their location in the human brain.

Fig. 15.1 The circuitry of fear.

Figure 15.1 highlights the crucial role the amygdala plays in the fear response. It is essentially the central processor of fear. The amygdala receives and transmits information from the external world (via the thalamus, ventral tegmental area, and reticular formation). It merges this information with our memory, senses, executive functions, endocrine and musculoskeletal systems (via the hippocampus, sensory/motor cortex, association cortex, hypothalamus and brainstem) to elicit a complex emotional and behavioral response.

In humans, the amygdala is thought to be essential for the recognition of threatening environmental cues and modulation of the emotional response to them. Neuroimaging experiments of normal human brains show that the amygdala is important in our ability to recognize and respond to threatening stimuli in the form of disturbing faces, gestures, and scenes that evoke fear.^2,³ This basic finding corresponds to the deficits observed in persons with surgical destruction of the amygdala and children with autism. In both cases, there is an enormous deficit in the individual’s ability to accurately identify and respond to fear-evoking stimuli.^4,⁵

Other experiments have suggested the amygdala also plays an important role in the development of chronic anxiety and pain. One study has found that activation of the basolateral nucleus of the amygdala causes the emotional experience of anxiety without a corresponding increase in heart rate (which is controlled by the hypothalamus via a separate pathway).⁶ There is growing evidence that the amygdala plays a crucial role in the up- or downregulation of the emotional response to pain and that this ‘nociceptive amygdala’ can be influenced by a wide range of environmental and internal stimuli to modulate the subjective experience of pain.⁷

The hippocampus, a structure with robust connections to the amygdala, is a center for memory formation, storage, and retrieval. It provides information from detailed memories that are processed by the amygdala and given a particular emotional value. The emotional value the amygdala places on a particular memory is then fed back to the hippocampus, where it integrates this information and either strengthens or weakens the memory. This is why it is believed that events associated with high emotional content (a car accident, being wounded in battle, one’s first kiss) tend to be remembered in greater detail than those with little emotional significance (the drive to work every morning). In persons with bilateral destruction of the hippocampus secondary to herpes encephalitis, there is a preservation of memory related to processes (such as tying shoes, using a fork), but a deficit in memory related to particular events, persons, and experiences along with mood problems.^8,⁹

In persons with post-traumatic stress disorder (PTSD), changes are seen in the amygdala, hippocampus, and other areas of the limbic system (the neural circuits of complex emotional experience). Neuroimaging studies have found consistent reductions in either total hippocampal volume or blood flow in men and women with PTSD.¹⁰^–¹³ The primary function of the hypothalamus is to regulate the body’s homeostatic and endocrine systems. In relation to the fear response, the hypothalamus sends projections to the medulla which controls autonomic (fight-or-flight) functions such as heart rate, muscle tone, digestion, sweating, etc.¹⁴ With input from the amygdala, the hypothalamus contributes the hormonal and autonomic component of the fear response.

The ventral tegmental area (VTA) and reticular formation (RF) are brainstem structures with projections throughout the brain. These structures are rich in dopaminergic (VTA), noradrenergic (locus coeruleus), and serotinergic (raphe nuclei) neurons. The role of neurotransmitters will be discussed in greater detail later in this chapter.

Research on other structures within this fear circuit has expanded our understanding of how the cortical structures influence the amygdala. Human brain imaging studies have found that the fusiform gyrus, prefrontal, and anterior cingulate gyrus are preferentially activated in response to fearful stimuli.^3,¹⁵ The orbitofrontal cortex (OFC), which is involved in the evaluation of risk and reward and social norms, may also have a direct role in regulation of anxiety via its connection to the amygdala (Fig. 15.2).¹⁶ The cortex, then, plays an essential role in the categorization, appraisal, and attenuation of our reactions to fearful stimuli. The higher cortical connections to the more primitive fight, flight, and reward circuitry is what allows humans to have a degree of conscious recognition and control over these processes. These connections and their conditioning form the biological basis for the effects of behavioral training used widely in the treatment of pain, such as relaxation and biofeedback.

Fig. 15.2 Serotonin (5-HT) and norepinephrine inhibit painful physical symptoms.

More recent functional brain chemistry research has provided neuroanatomical evidence for the overlap between the processing and perception of pain and anxiety. In an experiment comparing patients with chronic low back pain (CLBP) to normal controls, significant differences were found in two regions of the association cortex (orbitofrontal [OFC] and dorsolateral prefrontal cortex [DLPFC]), cingulate gyrus (part of the limbic system), and thalamus.¹⁷ The study showed that persons with CLBP have differences in regional brain chemistry in the OFC and DLPFC when comparing their perception of pain. Additionally, persons with CLBP and anxiety had changes in brain chemistry suggesting increased interaction between all four brain regions, whereas anxious controls only had changes observed in the OFC. Anxiety and pain, therefore, share common neurochemical pathways and can interact in a way that leads to the reorganization of normal perceptual pathways in the brain.

Role of neurotransmitters

Well over 300 different chemicals have been identified as ‘neurotransmitters.’ Endogenous neurotransmitters are broadly defined as chemicals synthesized in neurons, released in response to electrical impulses and acting on other neurons to cause changes in their electrochemical properties.¹⁷

There are three major classes of neurotransmitters: biogenic amines, amino acids and peptides. All three classes are relevant to our discussion, but we will limit our discussion to the biogenic amine and amino acid neurotransmitters because they are most relevant to the topic of anxiety. The major biogenic amines acting within the fear circuit are dopamine (DA), serotonin (5-HT) and norepinephrine (NE).

Biogenic amines

Dopamine

The VTA sends dopaminergic projections throughout the brain. The VTA is primarily associated with reward and its connections with the nucleus accumbens are believed to be at the heart of the reinforcing effects of drugs of abuse.¹⁸ The VTA’s dopaminergic projections to the amygdala and hippocampus are the areas in which the reward circuit influences the emotional and memory-forming structures in the brain. The VTA is also regulated by the amino acid neurotransmitter GABA (γ-aminobutyric acid) and opioid peptide neurotransmitters (enkephalins, endorphins). This convergence of GABAergic and opioid peptide receptors with the dopaminergic neurons of the VTA may be an important pathway in the development of benzodiazepine and opiate addiction.

Serotonin and norepinephrine

The cell bodies of 5-HT and NE neurons are located in the dorsal raphe nuclei and locus ceruleus, respectively. Like the DA neurons of the VTA, the 5-HT and NE neurons have diffuse projections throughout the brain. Drugs such as tricyclic antidepressants (TCAs), and selective serotonin reuptake inhibitors (SSRIs) have been used to treat mood disorders for the last several decades. Although the exact mechanism of how these drugs act to produce therapeutic efficacy is unknown, the central role of 5-HT and NE in chronic mood disorders (especially major depression and anxiety disorders) is strongly supported by the weight of controlled trials supporting the efficacy of drugs that act directly on these neurotransmitter systems.

There is a growing body of research that supports the role of 5-HT in modulating the amygdala and other limbic structures in persons with chronic anxiety disorders. Specifically, the SSRI drug paroxetine (Paxil) has been associated with a reduction of amygdala volume in persons with obsessive compulsive disorder (OCD), an anxiety disorder believed to be associated with a hyperactive amygdala.¹⁹ Conversely, in persons with PTSD, increases in hippocampal volume are positively associated with paroxetine treatment.²⁰

A study examining the effects of tryptophan (the dietary amino acid precursor of 5-HT) depletion found decreases in the ability to recognize fear-related cues.²¹ Allelic variations in amygdalar 5-HT transporter proteins have also been found to correlate with individual responses to fear-related cues.²² Severe acute pain activates stress-related noradrenergic systems in the brain. Descending projections to the sympathetic nervous system may cause increased firing of pain neurons through several mechanisms as well as nociceptor activation and muscle tension and spasm. Ascending noradrenergic projections to the forebrain cause cognitive–emotional reactions, such as fear and anxiety, which to some degree are contextually determined. For example, pain in childbirth often does not evoke fear or anxiety, whereas pain in traumatic spinal and/or limb injury, with uncertain outcome, often does. The association of pain, anxiety, and depression may have a common neurochemical substrate in the serotonergic systems.

Amino acids

Glycine and GABA are amino acid neurotransmitters. Glycine is known as the primary excitatory neurotransmitter in the brain. GABA is the primary inhibitory neurotransmitter in the brain. Together, glycine and GABA are the most common endogenous neurotransmitters and 75–90% of all neurons in the CNS have glycine and GABA receptors.¹⁷ A thorough discussion of the biology of glycine and GABA is beyond the scope of this chapter. However, it is important to discuss the basic biology of GABA in the context of this chapter because of its central role in the action of benzodiazepines.

GABA

As mentioned previously, GABA is the primary inhibitory neurotransmitter in the CNS. It is estimated that 30% of all CNS synapses use GABA as a neurotransmitter and it is found in very high concentrations in CNS tissues (1000 to 1 000 000 times greater than concentrations of biogenic amines).²³ The synaptic receptor for GABA is composed of two major receptor subtypes known as the GABA_A and GABA_B receptors. All benzodiazepines work at the GABA_A receptor. Rather than occupying the entire GABA receptor as a competitive agonist (like morphine’s action at the opioid receptor), benzodiazepines bind to the GABA_A subunit and actually facilitate endogenous GABA binding at the GABA_A receptor. GABA_A receptor activation opens chloride ion channels which hyperpolarizes neuronal membranes and inhibits firing (Fig. 15.3).²³ This elegant mechanism is believed to be the primary pathway for the anxiolytic effects of benzodiazepines. Psychoactive compounds such as barbiturates and ethanol also act at the GABA receptor to produce similar anxiolytic and CNS depressant effects.

Fig. 15.3 Subunit structure and pharmacology of the GABA_A receptor.

In an interesting study of the effects of benzodiazepines in acute pain, Di Piero and colleagues studied cerebral blood flow (CBF) by single photon emission computed tomography (SPECT), with and without diazepam.²⁴ Diazepam, a benzodiazepine, binds to the benzodiazepine receptor on the GABA_A receptor site and enhances GABA’s opening of the chloride channel, activating the GABA system and its anxiolytic actions. Diazepam, when given to healthy volunteers, following induction of pain by the cold pressor test (CPT), inhibited activation of the temporal regions, which was interpreted as part of the affective–emotional component of pain response. Diazepam-treated subjects tolerated the pain better and on SPECT this was associated with lack of temporal lobe activation of sensory–discriminative pain-related brain regions (contralateral hand region in the sensory motor cortex, pre-motor cortex and thalamus, and left anterior cingulate gyrus). This activity suggests that diazepam, which is useful in managing acute anxiety, interferes with affective–emotional components of pain perception and modifies temporal lobe activation patterns. The role of benzodiazepines in the treatment of acute and chronic anxiety will be discussed later in this chapter as will issues related to tolerance, dependence, and addiction to these medications.

DIAGNOSIS OF ANXIETY DISORDERS

Introduction

There are two major national surveys that estimated the prevalence of anxiety disorders in the United States. The Epidemiologic Catchment Area study estimated that 7% of people in the United States have a clinically significant anxiety disorder.²⁵ The National Comorbidity Study (NCS) reported even higher prevalence rates for anxiety disorders. NCS estimated 12 month prevalence rates of 17.7% for at least one anxiety disorder and lifetime prevalence rates near 25%.¹

The majority of persons with anxiety disorders suffer from simple phobias (i.e. needles, insects, heights). The NCS estimated the lifetime prevalence of generalized anxiety disorder (4.1–6.6%), PTSD (1.0–9.3%), panic disorder (2.3–2.7%), and social phobia (2.6–13.3%). The prevalence of any current psychiatric disorder in one survey of a large city spine clinic was estimated to be 59% and as high as 77% for lifetime prevalence.²⁵ Of those with chronic anxiety disorders, 95% had evidence of a disorder before the onset of back pain.²⁶ This strongly supports the need to carefully screen for anxiety disorders at the time of first intake to a spine clinic and to integrate treatment for anxiety disorders into the comprehensive treatment plan.

Clinical vignette 1: A case of untreated obsessive compulsive disorder

Pain medicine is asked to consult on a 38-year-old married disabled healthcare worker hospitalized for recurrent gastric bleeding. She has undergone two surgeries for gastric bleeds and suffers from dumping syndrome. On this admission she requires ice lavages for homeostasis, but avoids a third surgery. She also complains of neck and upper extremity pain which has been persistent since a discectomy for a herniated cervical disc 11 years before, when she suffered terrible pain postoperatively in hospital. Since then she has subsequently engaged in daily compulsive postprandial use of NSAIDs to control pain, starting 1 year prior to cervical spine surgery. She never discussed this behavioral pattern with her physicians. Further evaluation reveals a 15-year history of repetitive ritualized hand washing and housecleaning for hours daily, aggravating radicular and myofascial pain. The diagnoses of obsessive–compulsive disorder (OCD) and secondary major depression are made. OCD requires intensive treatment with SSRIs, cognitive behavioral therapy, and couples therapy over 1 year, with follow-up supportive psychotherapy. The patient stops NSAID abuse and her chronic gastric ulcers gradually heal. She also reduces daily hours of ritualized cleaning, and radiculopathy is now controlled with routine use of gabapentin, long-acting oxycodone, and occasional trigger point injections for myofascial pain. She functions well at home although is unable to return to work. Two years later when she gradually develops progressive symptoms and signs of cervical myelopathy, an MRI is recommended. The patient is frightened that an MRI will lead to surgery, and avoids this for 6 months. Finally, she agrees to premedication with clonazepam for 3 days, and accompanied by the pain management nurse, whom she likes and trusts, successfully completes the MRI which reveals cord compression. Surgical decompression and fusion is recommended; however, terrified of the prospect of another surgery, which recalls the terrible postoperative pain of her first surgery, she refuses to consider surgery as an option.

This case illustrates post-traumatic phobic anxiety complicating poorly managed acute postoperative pain as well as, the activation of a premorbid anxiety disorder, in this case OCD, with almost fatal consequences. Furthermore, her long history of undiagnosed and untreated ritualized hand washing and housecleaning caused by OCD certainly worsened cervical radiculopathy. Now, her residual phobic anxiety, resulting from poorly managed postoperative pain years ago, causes her to refuse consideration of needed spine surgery. This is a case in which appropriate postoperative pain pharmacotherapy and early screening and diagnosis for a chronic anxiety disorder might have prevented such an outcome.

Evaluation of clinical anxiety

The DSM IV-TR lists the following anxiety disorders: panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific and social phobias, obsessive–compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to general medical condition, substance-induced anxiety disorders, and anxiety disorders not otherwise classified. Going through this list of anxiety disorders, it is easy to imagine how these disorders can complicate a pain disorder and vice versa.

Table 15.2 lists major anxiety disorders recognized in DSM IV-TR along with questions that can help a clinician screen for anxiety disorders. An affirmative answer to these questions should prompt a clinician to obtain further history, treat, or prompt a referral to a mental health professional.

Table 15.2 Screening Questions for Common Anxiety Disorders

Panic disorder with and without agoraphobia

‘Do you ever have panic attacks?’

‘Do you ever get attacks where you suddenly feel terrified or like you are about to die?”’

‘Do you ever suddenly feel overwhelmed to the point where you become physically ill?’

‘Do you ever feel afraid to go out of the house because you are worried about becoming overwhelmed or having an attack in front of people?’

Generalized anxiety disorder

‘Are you a chronic worrier?’

‘Do you worry about things you really can’t control?’

‘When you worry, do you get physically ill or uncomfortable?’

Obsessive–compulsive disorder

‘Do you worry excessively about:

being dirty or contaminated with germs?

doing certain things exactly the same way?’

‘Do you feel like you have to do certain things over and over again, such as:

wash your hands, shower?

count or check things?

say certain words?’

‘Is it hard to stop thinking about (obsessive thought)?’

‘Is it hard to keep yourself from (compulsive behavior)?’

Post-traumatic stress disorder

‘Have you ever been in a situation where you, or someone close to you, was almost killed, injured, or threatened in a way that caused you to feel terrified or extremely emotional?’

Some experiences to ask about:

sexual trauma

combat experience

witnessing death and destruction

physical assault

‘Do you feel like you’ve never quite gotten over (traumatic event)?’

‘Did you ever feel back to normal after you experienced (traumatic event)?’

‘Do you have dreams or disturbing thoughts about (traumatic event)?’

Specific phobia

‘Are there any specific things such as animals, insects, needles, and heights that make you very nervous?’

‘Do you think your fear is more than normal?’

‘If were faced with it right now, do you think you could handle it?’

The assessment of anxiety should include a detailed medical, and selective physical and laboratory examination, and a history to exclude other medical conditions which can present with anxiety. Medical conditions that can present with symptoms of anxiety include neurological disorders (cerebral neoplasm, CVA), systemic conditions (hypoxia, hypoglycemia, cardiac arrhythmias, anemia) endocrine disturbances (thyroid, pituitary, parathyroid) and deficiency states (B₁₂, pellagra). In addition, it is also important to rule out anxiety secondary to medication effects or withdrawal, toxins, and psychoactive substance abuse. A common phenomenon is rebound pain and anxiety, which occurs when a patient with pain disorder takes short-acting analgesics frequently during the day, in the case of headache, often called ‘transform’ headache.

In patients with pain disorders, the physician must be alert to several situations that commonly precipitate anxiety: increases in pain; threat of withdrawal of workers’ compensation benefits; threat of job loss; threat of marital discord or even spousal desertion caused by the stress of pain and disability; fear of surgery; fear of worsening disease, particularly when increasing or new pain may indicate cancer recurrence or spread; withdrawal from medications that are abruptly stopped, including opioids, antidepressants, anticonvulsants, sedatives and benzodiazepines; withdrawal from alcohol; stimulant intoxication; side effects of certain medications, such as SSRIs, tricyclics, and theophylline derivatives used for asthma; and drug–drug interactions, such as serotonin syndrome.²⁷

INTRODUCTION AND GENERAL PRINCIPLES OF THE TREATMENT OF ANXIETY DISORDERS

General principles of biobehavioral medication use in chronic pain

The successful use of medications in chronic spine pain depends upon careful clinical reasoning, founded upon a working knowledge of the phenomenology and physiology of pain syndromes and anxiety disorders and the ability to assess how anxiety and pain interact in any one patient, to cause and perpetuate pain and functional disability. In any patient with spine disease, anxiety can:

• Activate neuropathic pain and muscle pain

• Interfere with concentration and effective coping strategies;

• Precipitate maladaptive coping such as poor decision-making, task avoidance, misuse of medications, or drug abuse.

To minimize the effects of anxiety on patients with chronic pain, physicians should routinely give patients behavioral tools for self-care and symptom management.²⁸ Simple behavioral interventions, such as asking a patient to keep a diary and handing them a relaxation tape with instructions for daily use, take little time and may pay large benefits. Diaries give the physician important information about the pattern of pain and anxiety over each 24 hour period – factors such as activities that increase the pain or anxiety, or factors such as medication or activity avoidance that prevent escalations of anxiety and pain. The effects of new medications against baseline anxiety and pain scores can document effectiveness more robustly than questions such as, ‘How effective is the medication?,’ which may lead to information subject to recall bias, and does not provide the detail needed for effective treatment decisions. Relaxation tapes help patients restore control over emotions in response to pain or to stress that activates neuropathic pain and also helps them relax muscle groups.

When patients become disabled by chronic pain, to counter the impact of emotional factors, such as anxiety, and negative conditioning, comprehensive integrated, biobehavioral pain rehabilitation programs are more effective than both conventional medical treatment or ‘alternative’ therapies,²⁹ for example, returning low back pain patients to work at a rate that is about 40% higher than conventional treatment.³⁰ The ability to orchestrate constructively the complex network of supportive relationships necessary to rehabilitate these patients is essential. Skills in pain and stress management, such as pharmacology and behavioral pharmacology, group therapy and psychotherapy, greatly complement the skills of the rest of the team. Pain management training, usually taking place in behavioral educational groups, complemented as needed by individual psychotherapies, is effective in chronic pain patients and can reduce medical visits and costs.³¹ The sequence of tasks in such a group work in conjunction with physical rehabilitation and pharmacotherapy to enable helpless-feeling, functionally impaired patients to develop a sense of control over their pain, their fear of activity and their anxiety.^28,³²

Psychotherapy for anxiety disorders

Empathic listening and reassurance are the cornerstones of therapy for acute and chronic anxiety disorders. In addition to, or instead of, medication, talk therapies such as cognitive behavioral therapy (CBT) have proven efficacy in the treatment of panic disorder, PTSD, and social anxiety disorder. Behavioral therapies such as progressive relaxation, meditation, proper sleep hygiene, and exercise also have been shown to improve depression and anxiety. Specific phobias (i.e. needle or other medical procedure phobias) respond very well to CBT that emphasizes graduated exposure to the fearful stimulus in a controlled environment. It is important to consider that severe forms of OCD, PTSD, panic disorder, and specific phobias may be so incapacitating that psychological and behavioral therapies, applied over a significant period of time, may be required in addition to medication.

The principles of CBT for anxiety and pain are similar, in that the practitioner focuses on helping the patient learn specific cognitive and behavioral coping skills to prevent, abort, or ameliorate symptoms – in this case, anxiety. In panic disorder, cognitive therapy challenges false beliefs and information about panic attacks and is used in conjunction with respiratory training, applied relaxation, and in vivo exposure and response prevention. In OCD, behavior therapy may be as effective as pharmacotherapy, with some suggestion that the beneficial effects are longer lasting, and together they are more effective than either alone. The principle behavioral approaches in OCD are exposure and response prevention. Desensitization, thought stopping, flooding, and aversive conditioning have also been used.

Clinical vignette 2: A man with chronic low back pain

Pain medicine is asked to evaluate a 36-year-old man for opioid pharmacotherapy after he continues to report back pain unresponsive to NSAIDs and a brief trial of gabapentin. The patient’s symptoms worsened dramatically after he received the results of his MRI report. At the time of his initial pain clinic assessment, the patient, obviously anxious and sullen, reported little hope for a return to his previous level of functioning saying, ‘I’m going to wind up in a wheelchair by the time I’m fifty.’ When asked to say how he came to this conclusion, the patient reported, ‘The MRI, it says I have “degenerative changes” and my doctor told me it’s worse than what I had 3 years ago.’ After the patient was allowed to discuss his thoughts and fears about this, he was asked if he’d like to just go over the results of his MRI report again, this time with the opportunity to ask questions about the report.

The patient was clearly preoccupied with the terms ‘degenerative’ and ‘arthropathy’ and took them to mean that he suffered from a severe, incurable skeletal disease that would leave him permanently disabled, well before his time. After a simple explanation of the medical jargon on the report and what the spine of a person his age looks like, the patient was able to realize that, in fact, the results of his MRI were within the normal limits for his age and amount of physical activity. Further questioning revealed that he was in a major depressive episode, was having occasional panic attacks, and was coping with the stress of his wife, who was going through chemotherapy for ovarian cancer. The patient was started on an SSRI and a 1-week trial of clonazepam 1 mg b.i.d. with excellent results, and no initiation of opioids. The patient also self-initiated an at home exercise program and reported 75% improvement in his pain after 2 weeks.

This case clearly indicates how easily a communication gap between a patient and treating physician can quickly turn into a therapeutic chasm. The only ‘interventions’ in this case were 30 minutes of empathic listening, reassurance, and demystification of medical jargon, which led to three things: (1) richer understanding of the social and psychological irritants of the patient’s low back pain, (2) diagnosis and treatment of a mood and anxiety disorder, and (3) empowering the patient to take control of his rehabilitation.

Pharmacologic treatment of anxiety disorders

Anxiolytics for acute anxiety

Table 15.3 provides a list of medications that are commonly used to relieve acute anxiety. When trying to find a medication that is well suited for the purpose of relieving acute anxiety, the time of onset of peak anxiolytic effect is most important, and sometimes not at all related to the elimination half-life of the drug. For example, diazepam has a very long elimination half-life, but a peak anxiolytic effect on par with, or even superior to, alprazolam.

Table 15.3 Oral Medications for Acute Anxiety

Medications for chronic anxiety disorders

Antidepressants

Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) have important roles in the treatment of chronic anxiety disorders. Only venlafaxine (Effexor) extended-release (XR) has been shown to possess unequivocal efficacy in generalized anxiety disorder (GAD).^33,³⁴ Pharmacotherapy of post-traumatic stress disorder includes several antidepressants.³⁵^–³⁷ SSRIs protect against PTSD’s overwhelming intensity by modulating affect, memories, and impulses while loosening excessive inhibitions. Fluoxetine, fluvoxamine, sertraline, and paroxetine have all been FDA approved for the treatment of OCD. Higher doses may be necessary, such as fluoxetine 80 mg a day. The best outcomes are obtained when pharmacotherapy and behavior therapy are combined.³⁸ Social phobia responds well to SSRIs and propanalol, a β blocker, can be used preemptively to quell anxiety prior to a performance. For panic disorder, generally, start with an SSRI, such as citalopram, sertraline, or fluoxetine.³⁹ If a rapid control of anxiety symptoms is needed, a short acting benzodiazepine such as lorazepam should be used until the effects of SSRI are felt, keeping in mind the abuse potential and other potential negative effects of prolonged use of benzodiazepines. Once the SSRIs begin working, a benzodiazepine should be tapered and regular use avoided.

Medications approved for use in the treatment of chronic anxiety disorders are listed in Table 15.4, starting and maintenance doses of selected anxiolytics are listed in Table 15.5, and side effects of SSRIs are listed in Table 15.6.

Table 15.4 Effective Medications for Chronic Anxiety Disorders^a

Table 15.5 Starting and Maintenance Doses for Selected Anxiolytics

Table 15.6 Side Effects of SSRIs, Venlafaxine, and Duloxetine

Sexual inhibition
Diminished libido	Dose related.
Inhibited orgasm	50–80% incidence.
Gastrointestinal
Nausea/vomiting	Most frequent with sertraline, fluvoxamine and citalopram.
Diarrhea
Anorexia	Usually transient symptoms that resolve within 4 weeks.
Dyspepsia
Weight gain
Up to 30% of patients	Most common with paroxetine.
Headache
Fluoxetine most common	Usually subsides in 2–4 weeks.
Anxiety
Fluoxetine most common	Insomnia greatest with fluoxetine.
Insomnia/sedation
Helped by taking medication qam or qhs	Somnolence greatest with citalopram and paroxetine.
Dreams/nightmares
Seizures	Low incidence (0.1–0.2%).
	Increased risk with high doses.
Extrapyramidal symptoms	Mainly limited to fine tremor.
	Rarely causes dystonia or pseudoparkinsonism.
Anticholinergic
Dry mouth	Dose related. Most often with paroxetine. Much lower than with tricyclics.
Constipation
Sedation
Hypertension	Mild increases with higher doses (>150 mg) venlafaxine.
Withdrawal/discontinuation syndrome
Flu-like illness, dizziness, anxiety, paresthesias, migraine, insomnia	Abrupt withdrawal of short acting medication. Most common with paroxetine and fluvoxemine.
Serotonin syndrome
Diarrhea, restlessness, agitation, hyperreflexia, autonomic instability, myoclonus, seizure, delerium, coma	Potentially fatal. Maximum risk with MAO + SSRI combined. In patients with migraine headaches, caution when prescribing SSRIs and SNRIs with serotonin (5-HT 1b/1d) agonists, the so-called tryptans (e.g., sumatriptan and its successors).

Buspirone

Buspirone (Buspar) is a unique anxiolytic medication indicated for the treatment of GAD and anxiety related to major depression. It has a mechanism of action different from traditional antidepressants and benzodiazepines. Buspirone works as a partial agonist at two serotonin receptor subtypes (5-HT_1A and 5-HT₂) and as a combined agonist/antagonist at the dopamine D₂ receptor.³⁹

Buspirone is effective for the treatment of GAD in doses of 30 mg per day. Because of its short half-life, it is usually given three times a day, although some trials have found twice-daily dosing to be efficacious. Compared to benzodiazepines, it has the advantage of being nonsedating, and non-habit forming. It also is not associated with a withdrawal syndrome from abrupt discontinuation (a problem with benzodiazepines and some antidepressants).

The major side effects associated with buspirone are dizziness, headache, nausea, and occasional insomnia. Because it has few cognitive side effects and no significant sedation, it is relatively safe to use in elderly patients. Although buspirone has chemical and side effect profiles that should make it an ideal choice, its efficacy as an anxiolytic has been less dramatic in clinical studies. In particular, patients with a history of prior benzodiazepine use for anxiety, tend to have poor response to buspirone. The onset of clinical efficacy can be as long as 3 weeks, which some patients find unacceptable.

Benzodiazepines

This chapter advocates for the use of benzodiazepines to be limited to the treatment of anxiety associated with acute and/or anticipated stressors. Certain benzodiazepines have clinical trial data supporting their efficacy for the treatment of GAD and panic disorder. Nevertheless, it is important to weigh the risks of using benzodiazepines with the potential benefits, especially when using the medication for more than 4 weeks.

It is important to identify at-risk patients, such as an elderly person, a person with a history of substance abuse, a person on multiple medications, and significantly limit or totally eliminate the use of benzodiazepines for anything other than acute or brief, time-limited treatment.

There are invariably cases in which one inherits a patient who has been taking a benzodiazepine for years and absolutely refuses to discontinue the medication. In this instance, a common-sense approach is appropriate and it may be the better part of valor to avoid a direct confrontation in favor of watchful waiting and gathering clinical data to assess whether or not the patient is using benzodiazepines compulsively or having negative side effects (memory loss, falls, withdrawal, rebound anxiety). The use of a benzodiazepine as a hypnotic should almost never extend beyond 14 days.

Tolerance, withdrawal, and addiction

Perhaps the greatest clinical concern regarding the use of benzodiazepines for chronic anxiety or as a hypnotic is the potential for abuse and dependence. Although the vast majority of persons who are prescribed benzodiazepines do not go on to develop a clinically significant substance use disorder, regular use of benzodiazepines invariably causes physiologic tolerance (requiring larger amounts of a drug to achieve the same therapeutic effect) and withdrawal (a sign of physical dependence) if the medication is abruptly discontinued.^40,⁴¹

It is important to distinguish between the physiological states of tolerance and dependence and the complex physical, behavioral, and psychological syndrome of addiction. Addiction is a pattern of compulsive use that causes significant impairment in functioning and this use persists despite evidence of harm to the individual (which includes familial, occupational, and societal relationships) and/or a persistent desire to stop the drug. The following case provides a good example of how problems with benzodiazepines can develop over time and how an undertreated anxiety disorder can lead to the development of an addiction to benzodiazepines.

Clinical vignette 3: A patient with benzodiazepine dependence

Pain medicine requests the assistance of an addiction psychiatrist to assess a 48-year-old man whose urine drug screens occasionally come up positive for cocaine. The patient also tests positive for benzodiazepines, but this is not discussed in the clinic because he gets them from his regular doctors. The pain service is reluctant to discharge this patient because of cocaine use as he has been in the clinic for a long time and has severe chronic pain from steroid-induced avascular necrosis (AVN), bilateral hip fractures, and arm fractures with multiple repairs.

The addiction specialist does a thorough psychiatric evaluation and the patient reports that he uses cocaine recreationally about 2–4 times a year and has never met criteria for cocaine dependence. The patient also has a significant history of GAD. The patient, however, has been on three benzodiazepines for the last 4 years, ‘for my anxiety and to help me sleep.’ The patient, who saw his regular psychiatrist about 3 times a year, was getting clonazepam (Klonipin) for GAD and lorazepam (Ativan) for ‘breakthrough’ anxiety. The patient was getting temazepam (Restoril) from his PCP when he complained of trouble sleeping.

The patient reported that he frequently ran out of benzodiazepines, traded them with his wife who was also prescribed benzodiazepines, experienced intense rebound anxiety, and became tremulous and diaphoretic when he went more than a day without them. Furthermore, he reported that on at least two occasions in the last 3 months he fell a short distance off his front porch and at the shopping mall. He also reported buying alprazolam (Xanax) from friends when he ‘just couldn’t handle it anymore.’ Review of his medical record also showed that he was admitted for a seizure 2 years earlier.

After some discussion about his chronic, compulsive use of benzodiazepines and the risks associated with them, the patient agreed that his use of benzodiazepines was problematic. The patient reported previous unpleasant physical and cognitive side effects to both sertraline (Zoloft) and paroxetine (Paxil) and therefore did not want to consider another SSRI for GAD. The patient was persuaded to begin a trial of venlafaxine (Effexor XR), which he discontinued after 2 weeks, reporting similar problems he had with the SSRIs. The patient remained extremely reluctant to discontinue his use of benzodiazepines because he believed they were the only things that relieved his anxiety.

This case provides ample evidence that the patient suffers from an addiction, not to cocaine, but to benzodiazepines. He certainly meets criteria for cocaine abuse by virtue of the fact that he used it despite the recurrent problems this caused with the pain clinic. However, the clinical history indicates that he has a severe benzodiazepine addiction. Not only does he manifest features of tolerance and withdrawal (his seizure 2 years ago was probably secondary to benzodiazepine withdrawal), but he also has engaged in compulsive use, drug-seeking behavior, and suffered physical injuries while intoxicated.

A patient who has reached this level of compulsive use clearly needs the help of professionals trained in the management of addiction. However, ‘treatment’ for a benzodiazepine addiction can start when a clinician first recognizes it. Simple, nonjudgmental recognition of a compulsive pattern of drug use is the first step, followed by education about the risks associated with benzodiazepine abuse. Very often, such a brief intervention can accurately assess a patient’s motivation to come off benzodiazepines and lead to a plan of action for discontinuation or dose reduction of the medication.

Although there is no strict consensus on the best way to successfully taper and discontinue benzodiazepines, Table 15.7 provides some general principles to apply with both inpatient and outpatient populations.^40,⁴¹ Before initiating a benzodiazepine taper it is important to consider the following factors, which are associated with greater severity of withdrawal symptoms:

• High daily doses of benzodiazepines;

• Use of high-potency, short half-life benzodiazepines (i.e. alprazolam [Xanax]);

• Daily use for longer than 4 weeks;

• Female gender;

• High initial psychopathology.

Table 15.7 General Recommendations for Tapering Benzodiazepines ^32,³³

Try to switch the patient to an equivalent cross-tolerant dose of longer-acting benzodiazepine (i.e. 4 mg of lorazepam to 100 mg of chlordiazepoxide).

Usually favor a benzodiazepine that is longer acting and of lower potency than the current benzodiazepine with the following exceptions:

Elderly patients;

Persons with hepatic disease;

Persons with medical problems in which long-acting sedatives are undesirable or contraindicated;

Persons severely addicted to alprazolam;

The risk of withdrawal seizures is greatest with short-acting, high-potency benzodiazepines.

For patients addicted to alprazolam, first try to stabilize the patient on a cross-tolerant dose of clonazepam before trying to use a low potency benzodiazepine

Inpatient taper ¹

Reduce dose by 50% every 5 days;

Peak psychological withdrawal symptoms usually occur at one-fourth of the baseline dose;

Peak physical withdrawal symptoms usually occur at one-fourth to one-eighth of the starting dose.

Outpatient taper ²

Reduce baseline dose by 50% within 2–4 weeks;

Continue reduced dose for 8 weeks without a reduction;

After 8 weeks, decrease dose by one-eighth every 4–7 days until complete.

1 Brenner P, Wolf B, Rechlin T. Benzodiazepine dependence: detoxification under standardized conditions. Drug Alcoh Depend 1991; 29:195–204.

2 Rickels K, DeMartinins N, Rynn M. Pharmacologic strategies for discontinuing benzodiazepine treatment. J Clin Psychopharmacol 1999; 19(6 Suppl 2):12S–16S.

In these risk groups, the rate and duration of a benzodiazepine taper may be longer and associated with more physical and psychological complications. It may take some patients several months before they are able to successfully taper off a benzodiazepine.

Table 15.8 provides a list of equivalent dose ranges for commonly prescribed benzodiazepines that is useful for conversion to a long- or short-acting medication when tapering or optimizing a benzodiazepine regimen.

Table 15.8 Equivalent Benzodiazepine Dosing Chart (Based on Lorazepam Equivalents)

Benzodiazepine	Dosage	Half-Life^a
Lorazepam	1.0 mg	Short
Alprazolam	0.25 mg	Short
Triazolam	0.125 mg	Short
Temazepam	15.0 mg	Short
Oxazepam	30 mg	Short
Clonazepam	0.25 mg	Long
Clorazepate	3.75 mg	Long
Diazepam	5.0 mg	Long
Chlordiazepoxide	25.0 mg	Long