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5 Articles in Volume 4, Issue #1
Complications of Uncontrolled, Persistent Pain
Improving Postoperative Pain Outcomes
Peripheral Nerve Catheters for Acute Pain Control
The ABC's of Pain Clinic Referrals
Treatment-resistant Migraines

Complications of Uncontrolled, Persistent Pain

Persistent, unremitting pain may adversely affect the body’s endocrine, cardiovascular, immune, neurologic and musculo-skeletal systems and require aggressive treatment of the pain as well as the resulting complications.

To the unfortunate patient who is afflicted and the practitioner who treats it, incurable, persistent pain is truly its own disease regardless of its underlying cause.1-3 Persistent pain, which is also often characterized as chronic or intractable, has all the ramifications of a disease in that it may have pre-clinical and overt phases.4-6 It may be intermittent or constant, as well as, mild, moderate, or severe. The most unappreciated clinical feature of persistent pain, however, is the plethora of complications that may result — particularly if the pain is constant and unremitting.

Many recent and emerging studies clearly document that persistent pain exerts profound impacts on the body’s endocrine, cardiovascular, immune, neurologic and musculo-skeletal systems.7 Presented here is a review and classification of some of persistent pain’s complications to give the practitioner a basic understanding that persistent pain may produce a symptom complex or syndrome that must be recognized at the clinical level.1 Even though our understanding of the occurrence and mechanisms of the persistent pain syndrome are still quite limited, it is clear that the diagnosis and treatment of persistent pain’s complications must be simultaneous with pain treatment.

Deconditioning Complications

Any area of the anatomic body that experiences severe persistent pain will soon “decondition.” This area will cease normal, symmetric, coordinated movement, and the patient will simply self-splint, immobilize, and decondition the area. This leads to a number of complications including muscle atrophy, neuropathies, and in late stages, contractures. Muscle, nerve, and joint weakness, and deterioration result. It is not uncommon to see the patient with severe, uncontrolled pain progressively deteriorate due to muscle atrophy and contractures and go from cane to walker to wheelchair.

An unappreciated complication of deconditioning and immobility is obesity. Excess weight may further overload a painful, deconditioned anatomical site.

A single painful location on the body soon begets some others. Much of this is the “overload and overuse syndrome.” To make up for a weak, painful area, joints, nerves, and muscles elsewhere in the anatomy will attempt to compensate and work overtime. Unfortunately, chronic overuse and overload may lead to tissue degeneration at secondary pain sites causing arthropathies, myopathies and neuropathies. Pain patients sometimes develop a more painful secondary site than the primary site. The astute practitioner can often observe physical evidence of overuse, overload, and self-splinting such as the presence of hypertrophy of paraspinal or neck muscles, unilateral furrows of the brow in the persistent headache patient, and calluses on the foot in the patient with back, hip, or leg pains.

Hormonal Complications

Based on emerging research data, it appears that uncontrolled persistent pain may affect about every endocrine system in the body.8-11 It has long been observed that acute pain is often accompanied by hypertension and tachycardia, and it is now clear that persistent pain may actually trigger indolent hypertension and tachycardia.12 Excess catecholamine and glucocorticoid production is certainly contributory to these complications, but there may also be a stimulatory neurologic etiology caused by uncontrolled pain. Insulin and lipid metabolism may be altered, and recent studies with spinal cord injuries and systemic lupus erythematosis suggest that persistent pain may accelerate the atherogenic process.13,14 Cardiovascular death is a common occurrence among persistent pain patients likely due to a multitude of factors.

The impact of persistent pain on the hypothalmic-pituitary-adrenal-axis is profound and paramount to understanding the complications of persistent pain.7,15-18 Severe pain is a potent stressor — perhaps the most potent — that stimulates this system.7 Persistent pain initially produces excess secretion and high serum concentrations of catecholamines and glucocorticoids as the body attempts to control pain and prevent damage.12,18 If severe, persistent pain isn’t controlled, adrenal exhaustion and decreased serum levels of glucocorticoids, including cortisol and pregnenolone, may result.17,18 Even though the adverse affects of persistent pain on the pituitary thyroid, pancreas, pineal, testes, and ovary are less clear, all are likely impacted.8 Although the complex assault on the endocrine systems of the body by persistent pain begs for more research, it is clear that the severe, persistent pain patient may experience all the ramifications of excess and/or deficiency of glucocorticoids.19 Excess and deficient serum levels of glucocorticoids, often known as Cushing and Addison syndromes, respectively, manifest a diverse range of signs and symptoms in patients having severe, persistent pain. Table 1 presents a compilation of the signs and symptoms of these conditions. Note that patients with severe persistent pain may demonstrate either glucocorticoid excess or deficiency. Apparently, persistent pain patients can go from excess to deficiency states over time and demonstrate both states.10,11 Abnormal glucocorticoid states may have debilitating consequences including mental deficiencies, muscle weakness, edema, osteoporosis, diabetes, and stone formulation among others. Also, likely related to glucocorticoid abnormalities is the common observation of severe tooth erosion and decay. Furthermore, abnormal glucocorticoid levels likely interfere with pain control.15,16

Classification of Major Complications of Persistent Pain


  1. “Overuse” of ancillary musculoskeletal tissue with degeneration
  2. Decreased mobility
  3. Obesity
  4. Muscle atrophy
  5. Contractures
  6. Neuropathies


  1. Excess catecholamine production with hypertension and tachycardia
  2. Glucocorticoid excess or deficiency
  3. Hypotestosteronemia
  4. Insulin - Lipid abnormalities
  5. Immune suppression


  1. Nerve - Spinal cord degeneration
  2. Cerebral atrophy
  3. Depression/suicide
  4. Insomnia
  5. Attention deficit
  6. Memory loss
  7. Cognitive decline

Table 1. Classification of major complications of persistent pain

Hypotestosteronemia is now recognized as a common complication in persistent pain patients — both male and female. Opioid treatment potentiates testosterone deficiency.20 Since testosterone is the major androgen in the body having tissue building and healing attributes, adequate serum levels are essential. Testosterone also interacts with endogenous opioids to provide pain relief, and it is essential for libido in both sexes.21 Fortunately, testosterone replacement is now a simple clinical procedure thanks to a number of available agents.

Immune suppression is present in the persistent pain patient.22,23 It is manifested clinically by poor resistance against infections and slow healing of wounds or injuries. Hormonal abnormalities are most likely responsible. At this time, little is known about pain’s affects on such hormones as glucagon, thyroid, insulin, growth hormone, estrogen, progesterone, and endorphins, but derangement of any of these — in addition to cortisol, pregnenolone, and testosterone — may adversely affect the immune system. Serum testing of persistent pain patients typically shows a variety of serum immune abnormalities. Opportunistic infection is another hallmark of a suppressed immune system. Persistent pain patients, particularly those with an autoimmune disease such as fibromyalgia or systemic lupus erythematosis, may develop infections such as chlamydia, cytomegalus, and herpes. It may be that the same nervous tissue the produces pain is so injured that it becomes fertile ground for viruses that like to invade nerves.

Neuropsychiatric Complications

Persistent pain generates excess electrical activity in peripheral nerves, spinal cord, and brain. This “hot wire” effect appears to cause degeneration of nerve tissue — particularly in the dorsal horn of the spinal column.24 A recent controlled study shows that low back pain patients may develop cerebral atrophy.25 It follows that dementia and other organic brain syndromes may result.

The problems of insomnia, depression, suicide, attention deficit, memory loss, and cognitive deficiencies are extremely common in persistent pain patients.4-6,26 The precise biologic mechanisms by which persistent pain causes these complications is not totally clear, but they likely occur due to multiple adverse biologic affects including neuroanatomical degeneration, hormonal abnormalities, and neurochemical depletions at synaptic junctions.

Clinical Management of Complications

Understanding of the diagnosis and management of persistent pain’s profound complications are at an early stage. Nevertheless, there are some basics that can be incorporated into management of the persistent pain patient. Functional assessment of “deconditioning” and “overload-overuse” deficiencies should be done at the initial physical examination. An exercise and prosthesis program to minimize the degeneration of ancillary tissues is critical if deficiencies are found. Routine blood pressure and pulse monitoring by the patient is helpful to gauge pain control. At-home blood pressure-pulse monitoring to help assess pain control can be very revealing. Blood pressure should be below 140/90 mmHg and resting pulse below 84 per minute. Mental evaluation to detect depression, attention deficit, insomnia, memory loss, and cognitive deficits is advised. Standard treatments for these complications are essential to provide an acceptable quality of life for pain patients. Screening patients for evidence of hormonal and lipid abnormalities is simple. Glucocorticoid and sex hormone function can be easily screened by a single, early morning fasting blood specimen to determine serum concentrations of cortisol, pregnenolone, and testosterone. Abnormal concentrations of cortisol or pregnenolone may indicate poor pain control. Low concentrations of any of these three hormones may require replacement when aggressive pain treatment isn’t successful in normalizing serum concentrations.17 As part of routine clinical monitoring, the practitioner should develop procedures and protocols to periodically assess the complications of uncontrolled pain. Treatment modalities should be aggressively pursued if previous complications worsen or new ones appear.

Signs and Symptoms of Glucocorticoid Abnormalities
Glucocorticoid Excess
Weight Gain Menstrual Irregularity Depression
Lethargy Cognitive Dysfunction Memory Loss
Osteoporosis Paranoia/Psychosis Back Ache
Fractures Muscle Weakness Hypertension
Bruising Striae Loss Scalp Hair
Ankle Edema Renal Calculi  
Diabetes/Decreased Glucose Tolerance
Glucocorticoid Deficiency
Weakness Fatigue/Tiredness Salt Craving
Weight Loss Constipation/Diarrhea Tachycardia
Hyperpigmentation Nausea/Vomiting/Anorexia Anemia
Postural Dizziness Vitiligo Muscle/Joint Pains
Auricular Calcification Hypokalemia Hyponatremia
Hypotension (<110mm Hg Systolic)

Table 2. Signs and symptoms of glucocorticoid abnormalities19


Severe incurable, persistent pain will invariably produce a number of complications like any other disease. While complications have been categorized here as deconditioning, hormonal, and neuropsychiatric, future research and clinical experience may provide a more useful and detailed classification. Even more important is that our knowledge and understanding of pain complications is at an early phase, and it is critical that we move this early phase into one of better understanding for practical, clinical application.

Figure 1. Biological stress response from persistent pain.

It is certainly proper to refer to severe persistent pain as a disease or syndrome.1 The pain practitioner will need to assess the pain patient for complications and develop strategies to simultaneously control persistent pain and its debilitating, often lethal, complications.5

Last updated on: January 28, 2012
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