Autonomically mediated pain (AMP) is a component of neuropathic pain controlled by the two divisions of the autonomic nervous system. Sympathetically mediated pain (SMP) is identified clinically as pain that does not follow a specific dermatomal distribution but can be relieved through sympathetic efferent blockade.1 The parasympathetic nervous system has yet to be implicated. SMP is contrasted with sympathetically independent pain (SIP), which is unaffected by the activity of sympathetic efferents.
Sympathetic autonomic responses to noxious stimuli result from nociceptive rather than from perceptual processes.
This supports the concept of pain and emotion in which sensory, motor, and autonomic components are partially independent processes that together shape emotional and painful experiences.22 SMP has many causes, with trauma being the most common. SMP can refer to complex regional pain syndrome (CRPS) type I (no verified nerve lesion) and type II (with verified nerve lesion), posttraumatic neuralgia, phantom limb pain, and acute herpes zoster (HZ).35
Epidemiology including risk factors and primary prevention
Epidemiologic data is not readily available due to poorly defined pathophysiology. Overall, there is an incidence of approximately 259,000 new cases of autonomically mediated pain in the U.S annually. In 2007, CRPS incidence was estimated to be 26.2 new cases per 100,000 annually in the US. 2,13 Approximately 80% of the 200,000 new amputations in the US result in phantom limb pain. Postherpetic neuralgia (PHN) is estimated to occur in 8% of the 600,000 to 800,000 new HZ cases each year.3
A large retrospective study in the Netherlands found CRPS most commonly affecting women between 50-70 years of age.34
Chronic courses of CRPS typically involve spontaneous occurrence, younger age, and female gender. Immobility may be an independent risk factor. Other risk factors include migraines, asthma, osteoporosis and the use of ACE inhibitors, all of which may reflect an inflammatory disease state.33 Genetics factors may play a role. The HLA-DQ1 serotype is isolated with increased frequency among patients with CRPS type 1 and there is an increased incidence of CRPS in siblings.36,37
Though several mechanisms have been identified in both animal and human studies, the underlying pathophysiology remains unclear. Animal studies have shown that primary afferent nociceptors become sensitized to nociceptive stimuli by catecholaminergic sympathetic outflow. Human studies show sympathetic-induced catecholamine sensitivity following complete or partial nerve lesions. A1-adrenoreceptors are upregulated in the skin of CRPS II-affected limbs, potentially increasing the effects of sympathetic activation.33
In the early stages of CRPS, the sympathetic outflow to skin vasoconstrictors is inhibited, resulting in reduced perfusion in areas associated with spatial body perception, somatosensory cortex, and the limbic system. In later stages of CRPS, the cold limbs may reflect increased sympathetic nervous system (SNS) receptor sensitivity.35 Functional imaging studies exhibited increased perfusion in the motor cortex, a decrease of grey matter volume in pain-processing areas and cortical disruptions in regions associated with motor control and planning.27In one study, the intracutaneous application of norepinephrine into a symptomatic area in patients with posttraumatic neuralgia was shown to propagate allodynia and spontaneous pain that had previously been blocked with sympathetic blockade. 4,38 Other proposed mechanisms include: enhanced activity of osteoclasts and humoral factors and upregulation of proinflammatory mediators.16
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
Autonomic vasomotor control may contribute to clinical features of disease progression, including erythema, warmth, and skin and nail changes seen in patients with CRPS. Autonomic instability typically results in pseudomotor changes and hyperesthesia in the affected extremity over time. CRPS can progress from acute to dystrophic to atrophic stages with each stage lasting three to six months.
Specific secondary or associated conditions and complications
SMP can have systemic manifestations. Organs with exclusive or predominant autonomic control are more prone to dysfunction during autonomic dysregulation. Patients with CRPS were shown to be four times more likely to have a positive head-up tilt test than age- and sex-matched peers.5
Almost all patients with CRPS for more than five years suffer from gastroparesis; the most frequent complaint being early satiety and bloating. Additionally, diarrhea, irritable bowel disease symptomatology, and constipation are present in 90% of these patients.
Essentials of Assessment
History of trauma or surgery with concomitant hyperalgesia and allodynia may indicate an autonomically mediated pain state. Fractures are the most frequent etiology. Other common triggers are sprains, contusions, and immobilization for extended periods of time. Intravenous line placement in tandem with other minor procedures have been documented to cause SMP.39
Pain is the most common reported sensory symptom. Hyperesthesia, hyperalgesia, and allodynia are also common complaints. SMP symptoms occur almost exclusively in the extremities and face. Motor, sensory, and trophic changes progress with environmental and symptom progression. Vasomotor complaints include flushing or erythema in the affected limb(s). Sudomotor signs include increased perspiration in the affected limb(s).
Vasomotor and sudomotor abnormalities are common presentations, with a study finding 81% of patients with CRPS having visible edema in the affected limb(s) during the acute stage.5
- Inspection: changes in appearance of the involved area, including trophic changes, differences in hair and nail growth, muscular atrophy, deviations in skin turgor, swelling and color changes.
- Temperature Evaluation: Palpable temperature changes may not be detectable in early disease stages (objective testing).
- Edema: volumetric testing or bilateral circumference measurements
- Motor Evaluation: involuntary movements, dystonia, muscle weakness, atrophy, or limited range of active motion in the involved limb(s).
- Sensory Evaluation: A detailed sensory examination including the presence of allodynia and the anatomic pattern of any associated sensory abnormalities to light touch, deep touch, pain, and thermal stimulation.23
Imaging is not recommended as a diagnostic tool for diagnosing autonomically mediated pain states, however it may be helpful for ruling out other processes. Plain films in CRPS may show spotty osteoporotic changes at the juxta-articular parts of bones, by four to eight weeks after onset. Triple-phase bone scintigraphy with technetium-99m is used to diagnose CRPS with an increased tracer uptake in the mineralization phase (phase 3). MRI is used to exclude other disease processes. Thermography in the first six months may detect an increased temperature in excess of 0.9°C compared with the contralateral limb.6 Electrodiagnostic studies can be effective in localizing a nerve lesion when suspected.7
Supplemental assessment tools
Traditionally, SMP is assessed clinically by pain relief following sympathetic blockade. Peripheral sympathetic pathways have multiple locations where blockade is feasible, including the subarachnoid space, epidural space, paravertebral and prevertebral regions, peripheral nerves, and endings of postganglionic axons.
Additional objective tests include thermoregulatory sweat test, silastic imprint, sympathetic skin response, and quantitative sudomotor axon reflex test.
The Budapest criteria is specifically used for the diagnosis of CRPS:33
- Continuing pain disproportionate to any inciting event
- Must report at least one symptom in three of the four following categories
- Must report at least one sign at time of evaluation in two or more of the following categories:
- Sensory: hyperalgesia (to pin-prick) and/or allodynia (to light touch, deep somatic pressure, joint movement)
- Vasomotor: temperature asymmetry and/or skin color changes and/or skin color asymmetry
- Sudomotor or edema: edema and/or sweating changes and/or sweating asymmetry
- Motor or trophic: decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (nail, hair, skin)
- There is no other diagnosis that better explains the signs and symptoms.
Early predictions of outcomes
Overall, approximately 60-70% of patients will experience resolution of symptoms at 12 months. Some early outcome predictors may include vocational or psychologic status, medication consumption, family relationships, emotional distress, pain intensity, and objective initial physiotherapeutic response measures. Specifically, high pain intensity has been cited as an indicator of negative outcomes. Additionally, if patients have motor dysfunction during the early stages of the disease course the majority will continue to have motor dysfunction.37
Typical tools used for assessment include the McGill Pain Questionnaire-Short Form, Beck Depression Inventory, Treatment Outcomes in Pain Survey, State-Trait Anxiety Inventory, and Pain Disability Index.
Social role and social support system
There are many support groups available for patients with autonomically mediated pain. The proliferation of social media has increased awareness and accessibility to support groups. The American RSPHope website (RSDhope.org) currently lists 146 support groups nationally throughout the U.S.
Rehabilitation Management and Treatments
Available or current treatment guidelines
Concurrent physical and occupational therapy, and pain management are recommended for pain and edema control. Psychological support to assess patient motivation and adherence to and tolerance of therapies. Clinical education is important for recognition of condition at earlier stages and improved adherence. The average time to diagnose CRPS has been estimated by various authors at a range from nine months to three years.
At different disease stages
In the acute phase, early therapies include gentle active range of motion exercises, stretching, and strengthening. The predominant role of these therapies is to prevent the decreased joint and tendon range of motion that can lead to atrophy.15 Manage edema with limb elevation, retrograde massage, and, rarely, diuresis. Orthostatic hypotension management may include compression garments, lifestyle changes (eg, alcohol abstinence, improved fluid intake), and/or pharmacologic agents, including midodrine, pyridostigmine, epoetin, or caffeine.
Advance rehabilitation to stress loading, isotonic strengthening, desensitization, and aerobic conditioning. Adding recreational and vocational therapy can encourage use. Psychologic and/or coping factors may require attention; cognitive-based therapies are used most frequently. Formal psychological assessment is recommended for patients with CRPS with symptoms for more than six to eight weeks.6 Graded motor imagery has also been shown in a small randomized controlled trial to be effective in patients with type I CRPS, although the mechanisms are unclear.9
Topical agents have shown some transient relief, without clear impact on progression. CRPS is hypothesized to involve increased glutamate output that act on the NMDA receptors on second order neurons of the spinal cord. This results in central sensitization.40 The NMDA antagonistic effects of ketamine can reduce allodynia in patients with CRPS8 when used topically with less side effects than parenterally administered ketamine. Ketamine infusions appear to produce adequate short-term pain relief, less than three months.31 Systemic infusions with ketamine at subanesthetic doses and phentolamine have been used.11
Interventional treatments may include one or multiple diagnostic ganglion blocks followed by a more permanent lesioning with radio frequency or administration of a neurolytic agent. Sympathetic blocks can be used early in treatment of CRPS when combined with Physical Therapy.39 Ablation of the sympathetic ganglion is rarely performed at this time. Conventional spinal stimulators have been proven effective in refractory cases of CRPS in several clinical trials, but recent studies suggest that dorsal root ganglion (DRG) stimulators tend to have better coverage of the affected area and are better tolerated by patients.18,29 Peripheral nerve stimulation should be considered for CRPS II with symptoms in the distribution of a single peripheral nerve unresponsive to other modalities. It should not be considered in patients with CRPS involving an entire limb or extension to the trunk.41 Interventional modalities have their own set of risks, which may eclipse the risks of conservative management.
Coordination of care
Coordination of care between physiatry, pain specialists, neurology, primary care, behavioral health professionals, and physical, occupational, recreational, and vocational therapy is necessary. Effective coordination of care has been shown to increase patient motivation.10 Early diagnosis is key to the best outcomes. Patients can improve through treatment measures ranging from pharmacologic to physical and psychological measures.
Patient & family education
Patient and family education is an important tool in the multimodal approach to treating autonomically mediated pain.11 Outline of treatment modalities along with time frames of the various stages provide for improved clarity and expectations. Maintenance of a pain and functional diary can help monitor pain progression and treatment effect.
Objective and survey-based outcome measures currently exist for SMP. Grip strength via dynamometry is commonly used in type I CRPS; the McGill Pain Questionnaire-Short Form is used in chronic pain states, including neuropathic pain, and involves 22 items with pain descriptions rated on a 10-point scale. Brush allodynia is typically used for patients with type I CRPS. The visual analog scale measures disease progression and response to treatments and/or therapies.
After adequate pain control, a case report of dry needling and intra-articular joint injections helped improve motor recovery.23 Immunosuppressants, such as mycophenolate, have shown promise in decreasing skin sensitivity, improving function and quality of life in a subgroup of CRPS patients.17 Amputations have not shown to decrease the incidence of pain or recurrence of CRPS.
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
Obtaining a thorough history may provide clinical oversight. Trophic, sudomotor, and/or vasomotor changes, especially after a documented peripheral nerve injury, highly implicates a complex regional pain state. Phantom limb pain may have autonomic findings. Variability/inconsistency in the formal and observational testing may require re-examination. However, given the chronic and progressive nature of most SMP states, the likelihood of remission or cure with a given intervention should be weighed against the likelihood of improvement with conservative treatment.
Cutting Edge/ Emerging and Unique Concepts and Practice
Animal models have shown allodynic behavior differences among different strains of rats with similar spinal nerve lesioning. It has been postulated that there may be genetically specific predispositions to sympathetically maintained allodynic behavior and possible differences in adrenergic receptor expression. Patients that fail medical management and lifestyle changes are typically candidates for interventional procedures (eg, ganglion blockade, intravenous dissociative infusions). For those patients whose symptoms cannot be controlled through the aforementioned techniques, the implantation of a spinal cord stimulator or a peripheral nerve stimulator may provide long-lasting control of symptoms; however, the effectiveness of the spinal cord stimulator in controlling type I CRPS symptoms declines over time.12 Intrathecal delivery of analgesics by way of an implanted pump has been used as well. Other emerging treatment modalities include hyperbaric oxygen therapy, botulinum toxin-A, and low-dose Naltrexone.39
Gaps in the Evidence-Based Knowledge
Although multiple animal models have shown that afferent neurons can develop adrenergic sensitization after inflammation, trauma, or infection, the exact mechanism of adrenoreceptor sensitization in humans is not clear.
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Darryl L. Kaelin, MD, John Scott Adams, MD. Autonomically mediated pain-autonomic pain syndromes. 9/20/2014.
Previous Revision(s) of the Topic
Michael Bruce Furman, MD, Shannon Schultz, MD, MPH, and Vivek Babaria, DO. Autonomically mediated pain-autonomic pain syndromes. 6/29/2018.
Vivek Mukherjee, MD
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