The parasympathetics are involved in headache [11, 13]. Based on HRV-alone measures, migraineurs with disabling attacks may be prone to ANS hypofunction [13]. These findings suggest that ANS dysfunction may be either a risk factor for migraine headaches or a consequence of frequent disabling attacks. HRV-alone measures are mixed or total ANS measures which do not allow further differentiation of these findings; specific P&S measures are needed. Moreover, ANS dysfunction and migraine may share a common neural substrate [14], and headache and migraine pain may be accompanied by considerable autonomic reactions, which are dependent on sympathetic activity [10, 11]. Based on autonomic innervation of cranial blood vessels, clinical and experimental observations in migraineurs suggest that a general hyperexcitability could develop along nociceptive trigeminal neurons, allowing the activation of descending pathways that facilitate pain processing or the suppression of pathways that slow down pain transmission [4, 10]. Progressive dysfunction of central pain systems secondary to the repetition of attacks of the originating headache have been implicated in slowly transforming the process from an episodic condition into a chronic condition [4].

Quality of life is significantly reduced among patients with neuropathic pain. Chronic pain patients have difficulty initiating or maintaining sleep, and sleep deprivation exacerbates pain [12]. Sleep deprivation is associated with anxiety and depression, both of which also make sleep disturbances worse. Depression and daytime sleepiness are associated with PE [22]. To effectively manage the chronic pain patient (including those with neuropathic pain), assessment and subsequent treatment of all comorbidities associated with the condition is necessary [12]. Recognition of an association between the diverse nature of comorbidities and the common underlying role of the P or S nervous systems facilitates the treatment of all comorbidities.

The sympathetics are involved in somatosensory pain and CRPS [4, 10]. CRPS, for example, may develop as a complication of trauma to a plexus or plexus involvement in trauma. Sympathetic neurotransmitter release is compromised in the affected area, and signs of sympathetic deficit (e.g., a warm flushed limb) often evolve into signs of sympathetic overactivity (e.g., a cool moist limb) due to the development of adrenergic supersensitivity. Because the parasympathetics are known to be involved in maintaining proper tissue perfusion [29], interactions between the P and the S can cause swings in sympathetic activation. Communication between sympathetic and the sensory neurons that signal pain may contribute to CRPS [11]. In addition, sympathetic activity may retard normal healing by aggravating inflammation-associated vascular disturbances [11].

Fibromyalgia is a chronic, painful musculoskeletal disorder of unknown etiology or pathophysiology. Many studies have suggested ANS involvement in fibromyalgia syndrome and related disorders, including chronic fatigue syndrome, irritable bowel syndrome, and depression/anxiety disorders, and, via P and S dysfunction, the risk for cardiovascular morbidity and mortality [16, 20]. A significant negative correlation between Hamilton Depression Scale scores and abnormal autonomic activity exists in patients with major depression, suggesting a direct association which may contribute to the higher cardiac morbidity and mortality [20]. Patients with stable coronary heart disease, or those with a recent acute coronary event, have been found to have lower HRV, as have depressed patients when compared with their nondepressed counterparts [22]. Anxiety disorders are associated with significantly lower HRV [21]. Patients with chronic fatigue syndrome show alterations in autonomic function, including orthostatic intolerance, which may be explained by cardiovascular deconditioning, a post-viral idiopathic autonomic neuropathy (AN), or both [17]. The presence of reduced HRV in chronic fatigue syndrome during sleep, coupled with higher norepinephrine levels and lower plasma aldosterone suggest a state of sympathetic dominance and neuroendocrine alterations [18]. While treating autonomic imbalance associated with fibromyalgia often does not cure the disorder, it reduces associated comorbidities, improving the patient’s quality of life and often reducing the severity of fibromyalgia itself. In other words, by normalizing sleep habits and reducing depression, the patient seems to be able to better tolerate the pain associated with fibromyalgia.

Patients with rheumatic diseases often demonstrate ANS-related dysfunctions. Clinically, these diseases are characterized by pain (i.e., spontaneous, hyperalgesia, and allodynia), active movement disorders, including an increased physiologic tremor, abnormal regulation of blood flow and sweating, and edema and trophic changes of skin and subcutaneous tissues. The ANS is, in part, responsible for the regulation of blood flow and sweating. Abnormal regulation is indicative of P&S imbalance. Alterations of P&S balance may also be involved in the pathogenesis of rheumatic diseases [24].

Based on clinical and experimental observations in critical care, including intensive care and surgery, the sympathetic is involved in pain following trauma [3, 10]. Even in neonates, P&S imbalance is observed in response to painful procedures [9]. Pain therapies and anesthesia are also shown to affect autonomic activity. Low-dose fentanyl administration in healthy volunteers leads to decreases in sympathetic and overall ANS modulation, with a trend towards vagal (parasympathetic) activation [27]. Similar reductions in sympathetic activity have been seen in response to other opioids and analgesic agents.

From an autonomic perspective, pain management is predicated on the fact that pain is a stressor and the sympathetics respond to stress [4]. The parasympathetics are responsible for proper tissue and brain perfusion [3]. Based on these predicates, P&S monitoring differentiates non-physiologic (e.g., psychosomatic) pain from physiologic (e.g., somatic or sympathetically mediated) pain from complex pain syndromes (e.g., CRPS or fibromyalgia). Because non-physiologic pain is perceived, and therefore cortical, the brain stem autonomic (e.g., sympathetic) measures are normal to low (see Fig. 24.1). The graphs of Fig. 24.1 are the response plots from a multiparameter graph report (MPGR). The graphs, from top left to bottom right in order, present the following: the (resting) (“A”) baseline P&S monitoring results, the parasympathetic response to (“B”) deep breathing, the sympathetic response to (“D”) Valsalva, the P&S monitoring responses to (“F, stand”) PC, and the parasympathetic responses to Valsalva (left) and standing (right). The gray regions indicate normal responses. These are data from a 24-year-old pain patient with a history of opiates. The patient is well managed. The patient already has a history of opiates and is requesting additional pain medication. These data indicate that the patient’s request for additional therapy is not a physiologic response and, therefore, the request for additional therapy is not based on a physiologic response.

For physiologic pain (e.g., somatic pain), one or more of the brain stem sympathetic (Autonomic Assessment) measures are borderline high to high. In the case depicted in Fig. 24.2, the resting response (top left graph) demonstrates a “sympathetic dominance” or SE. With complex pain syndromes, comorbidities are involved, induced by, or exacerbated by, autonomic dysfunction. For example, CRPS with plexus damage may involve circulatory deficits leading to abnormal tissue profusion, causing parasympathetic overexcitation (PE; see Fig. 24.3, bottom two graphs). In this case, the PE is demonstrated upon standing with no report of dizziness or lightheadedness. PE may heighten sympathetic activity, causing a heightened sensitivity to pain. PE is also associated with GI upset, sleep disturbances, fatigue, depression, urogenital dysfunction, and dizziness. SE is associated with anxiety, hypertension, and heart disease. Even if a patient demonstrates autonomic neuropathy as measured by low autonomic levels, high sympathetic activity relative to parasympathetic activity will indicate a relative, resting SE (high SB) and possible pain. For a pain patient, high SB may suggest pain. If, upon follow-up, a pain patient demonstrates higher, absolute sympathetic activity, or high SB, then the percent increase indicates the percent increase in pain. Also, based on balance (SB), therapy may be titrated. The goal of therapy is to remove the stress of pain and normalize P&S activity, in other words to balance disease or disorder – including pain – and adverse lifestyle with therapy. If the patients’ SB is normal, then they are well maintained at rest and may not need additional therapy. If P&S imbalance persists in a pain patient, whether at rest or during challenge, then additional pain therapy may be needed (history dependent). For example, SE during Valsalva indicates activity-induced pain, typically upper body, including lower back. If (resting) SB is normal with Valsalva SE, then it needs to be known what types of activity may induce pain. If pain is affecting normal daily routine, then additional therapy is probably appropriate (see Fig. 24.4). If, however, pain is affecting nonroutine activity (e.g., recreational activity), then additional pain therapy may not be required, and the clinician may consider allowing the pain to limit the patient’s activity until the affected area is healed.

Figure 24.4 displays sample baseline and follow-up trend plots for a 47-year-old, female, chronic back pain patient with a history of oxycodone, requesting more pain medication. The trend plots show the six phases of the Autonomic Assessment study indicated by the letters “A” through “F.” The left trend plot displays the patient’s responses when reporting persistent pain and requesting more pain medication. The sympathetic (red) response to Valsalva (section “D”) is high (off the scale) indicating SE and supporting the request for more pain medication. The right trend plot displays the 3-month follow-up when the patient reports “pain-free.” This is a normal trend plot (compare with Fig. 24.5). Notice that even the follow-up assessment’s resting baseline (section “A”) and PC (section “F”) portions show less sympathetic activity with a more normal sympathetic response to PC at the beginning of the stand challenge.

Relieving all SE or PE suggests that all pain indices have been normalized. Relief may or may not involve prescription medications. PE includes low SB, or DB, and Valsalva or stand PE. SE includes high SB, or Valsalva or stand SE. Figure 24.6 depicts examples of SE and PE. In this figure, sample trend plots from two CRPS patients are presented. The left panel presents a patient diagnosed with CRPS from a shoulder injury, including brachial plexus damage. The patient demonstrates resting and Valsalva (sections “A” and “D,” respectively) PE and SE. The right panel presents a patient diagnosed with CRPS from a hip injury, including femoral plexus damage. The patient demonstrates Valsalva and stand (sections “D” and “F,” respectively) PE and SE.

As a measure of normalizing P&S responses associated with pain relief, P&S assessment can document progress towards successful rehabilitation. A caveat is that the stress of pain is additive to other SEs that may also be present. SE can result from hypertension, sleep apnea, anxiety, and other chronic diseases such as diabetes. Further, the effect of pain therapy is not to block sympathetic activity, it is only to reduce the stress of pain, thereby reducing sympathetic activity to what it would have been without the pain. Therefore, SEs and PEs must be considered in the context of the patient’s history. SEs due to pain and SEs due to comorbidities are differentiated through titration of therapy and by observing the patient as P&S assessment is performed. Typically, if after 3 months, upon follow-up P&S assessment, there is no significant change in P&S activity levels after pain therapy was titrated higher, then the remaining autonomic imbalances are not a result of pain. To reduce the risk of morbidity and mortality, the clinician may consider titrating higher sympathetic blockade (e.g., beta-blocker or antihypertensive) or lower parasympathetic blockade (anticholinergics, e.g., tricyclic antidepressants or SNRIs) to normalize SB and P&S challenge levels. The 3-month follow-up study for the patient with an injured brachial plexus is presented in Fig. 24.7 (compare with Fig. 24.6, left panel). The patient (38-year-old, female) also demonstrated hypertension, attention-deficit disorder (ADD), and gastric disorder. She was prescribed gabapentin (Neurontin, Pfizer), nonsteroidal anti-inflammatory drugs (NSAIDs), antihypertensives, and diuretics. Her previous history at the time of testing (see Table 24.1) documents a resting HR of 65 bpm and hypertension under control. Her resting BP was 123/66 mmHg. From the first test (see Fig. 24.6, left panel), her average resting autonomic state was normal (see Table 24.1): resting sympathetics = 6.41 bpm² (normal resting sympathetics, 1.0< LFa <10.0 bpm²), resting parasympathetics = 5.92 bpm² (normal resting parasympathetics, 1.0< RFa <10.0 bpm²), and SB = 1.01 bpm² (normal 0.4< SB <3.0). Her Valsalva state was high (see Table 24.1): sympathetic = 185.04 bpm² (normal Valsalva sympathetic for a 34-year-old, 13.81< LFa <151.87 bpm² [159]) and Valsalva parasympathetic = 63.27 bpm² (normal, age and baseline adjusted, Valsalva parasympathetic, RFa < 35.7 bpm²). PC was also problematic for this patient, due to her injury. She reports pain while trying to hold herself upright. Her PC autonomic state was abnormal (see Table 24.1): PC sympathetics = 11.52 bpm² (normal, baseline adjusted, PC sympathetics: 7.69< LFa <32.05 bpm²), and PC parasympathetics = 7.61 bpm² (normal, baseline adjusted, stand parasympathetics: RFa <5.92 bpm²). In this case, the SE and PE associated with CRPS are found in both the patient’s Valsalva and PC P&S responses. Her resting (baseline) responses are within normal limits. Follow-up testing (Fig. 24.7 and Table 24.1) presents her responses after 3 months on a methadone pump, as prescribed based on her first test. Upon follow-up testing, her resting HR and BP are 62 bpm and 119/65 mmHg, respectively, and she reports much less pain with more freedom to participate in physical therapy. Her resting sympathetic activity (2.51 bpm²) has decreased significantly, supporting her reports of relief. Her resting parasympathetic activity (4.39 bpm²) may still be higher than normal for her, as indicated by her low-normal SB (0.57). However, low normal is more appropriate for geriatric patients, and high normal is more appropriate for younger adults. This relative PE may be associated with persistent perfusion abnormalities from the plexus damage. All of the rest of her P&S responses are lower and normalized, suggesting relief from pain, both at rest and during activity. Also, from her follow-up test, the parasympathetic response to DB (section B) is low, indicating the first signs of autonomic dysfunction, perhaps due to the chronic pain.