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Two of the 11 case reports described severe, intractable pain that appeared to be the cause of adrenal failure and death.
By Forest Tennant, MD, DrPH
Adrenal failure or insufficiency is commonly referred to as Addison's Disease or Addison's Syndrome. Thomas Addison, MD, a physician at Guy's Hospital, in London, first described this syndrome in 1855 in a report entitled, On the Constitutional and Local Effects of Disease of the Supra-Renal Capsules.1
In the 5 years prior to writing his report, Dr. Addison identified 11 patients who had an unusual clinical disorder. According to Dr. Addison, "The leading and characteristic features of the morbid state … are anemia, general languor, debility, remarkable feebleness of the heart's action, irritability of the stomach, and a peculiar change of colour in the skin, occurring in the complexion with a diseased condition of the supra-renal capsule." (In later history, the name of the glands located at the top of the kidney were changed from supra-renal to adrenal.)
Extremely low levels of serum cortisol and other adrenal hormones have been detected in severe pain patients.2,3 These levels can become so low that they are life threatening. Hormone testing and treatment are becoming a more common component of pain management.4 Given the increasing role of hormone testing and treatment in pain management, I reviewed Dr. Addison's original 1855 report. Most interesting, 2 of his 11 cases of adrenal failure appeared to be due to intractable pain. The other 9 cases were apparently due to tuberculosis or carcinoma.
As part of his report, Dr. Addison had an artist draw a picture of 8 of his 11 patients as well as some internal organs removed at autopsy, which showed dark brown, pigmented, freckle-type lesions along with adrenal insufficiency (Figure 1).
Addison's Description of the Disease
The clinical description of adrenal failure, including skin discoloration and pigmentation, laid out by Dr. Addison is quite descriptive and eloquent. His verbatim description is given here.1
"The disease presents in the same general character... It occurs in both sexes, generally, but not exclusively, beyond the middle period of life, and so far as I present know, chiefly in persons of a somewhat large and bulky frame, and with a strongly-marked tendency to the formation of fat. It makes its approach in so slow and insidious a manner, that the patient can hardly fix a date to his earliest feeling of that languor, which is shortly to become so extreme…
The countenance gets pale, the whites of the eyes become pearly, the general frame flabby rather than wasted; the pulse perhaps large, but remarkably soft and compressible, and occasionally with a slight jerk, especially under the slightest excitement; there is an increasing indisposition to exertion, with an uncomfortable feeling of faintness or breathlessness on attempting it; the heart is readily made to palpitate; the whole surface of the body presents a blanched, smooth, and waxy appearance; the lips, gums, and tongue seem bloodless; the flabbiness of the solids increases; the appetite fails; extreme languor and faintness supervene, breathlessness and palpitations being produced by the most trifling exertion or emotion; some slight edema is probably perceived about the ankles…
The debility becomes extreme, the patient can no longer rise from his bed, the mind occasionally wanders, he falls into a prostrate and half-torpid state, and at length expires: nevertheless to the very last, and after a sickness of perhaps several months' duration, the bulkiness of the general frame and the amount of obesity often present a most striking contrast to the failure and exhaustion observable in every other respect."
In his narrative, Dr. Addison was particularly impressed with the skin discoloration and pigmentation of his patients. He wrote about it with an emphasis indicating that this was a sign for physicians to observe and diagnose the condition while the patient was still alive.
"We discover a most remarkable, and, so far as I know, characteristic discoloration taking place in the skin—sufficiently marked indeed as generally to have attracted the attention of the patient himself, or of the patient's friends. This discoloration pervades the whole surface of the body, but is commonly most strongly manifested on the face, neck, superior extremities, penis and scrotum, and in the flexures of the axillae and around the naval. It may be said to present a dingy or smoky appearance, or various tints or shades of deep amber or chestnut-brown…
In some instances this discoloration occurs in patches, or perhaps rather certain parts are so much darker than others, as to impart to the surface a mottled or somewhat checkered appearance."
Dr. Addison called attention to pigment cell abnormalities that manifested in the form of "small black spots," which were on the skin as well as on some internal organs.
Addison Case #1
Henry Patten was a 26-year-old carpenter and window-blind maker admitted to Guy's Hospital on November 9, 1854. Up to 6 months prior, the patient stated that he enjoyed very good health. Then he began to be troubled with "rheumatic" pains in the right leg, which, without laying him up, gradually extended to the hips and side, and thence to the bottom of the spine.
Latterly, he described his back as very tender—a jerk or jarring movement caused great pain. For the month preceding hospitalization, he discontinued work due to attacks of "giddiness and dimness of sight, accompanied by a peculiar pain in the back of the head and partial loss of consciousness." These attacks would occur several times a day, usually upon exertion, upon standing, and were instantly relieved by sitting or lying down.
"Over the face and forehead, which are of a general yellowish hue, are several patches of darkened skin and similar black patches on the lips," continued Dr. Addison (Figure 2). "There is angular curvature at the second, and great tenderness on pressure over the upper three lumbar vertebrae; he complains also of pain at this part upon moving in bed."
In the 3 days before he died, the patient developed an incessant hiccough and pain "about the waist," which was later found to be a psoas abscess on the right side, "extending from Poupart's ligament to the disease vertebrae, and holding about a pint of flaky pus."
Dr. Addison wrote the following about Mr. Patton's autopsy findings: "the [abscess] was between the first and second vertebrae, commencing in the cartilage, and nearly destroying the neighboring vertebrae at their centers. The bone surrounding the cavity was red, soft, and infiltrated with strumous matter…Each supra-renal capsule was completely destroyed and converted into a mass of strumous disease." (Figure 3)
The report concluded by saying that the patient "labored under a serious affection of the spine," and the symptoms were also indicative of the clinical syndrome found with adrenal failure.
John Iveson was a 22-year-old stone mason who was admitted to Guy's Hospital on March 20, 1854, and died the following day. (Figure 4) He had a one-year history of severe abdominal pain, vomiting, and "tic douloureux." On admission to the hospital, the patient's extremities were cold, he had a very weak pulse, "his hands were blue, he had slight pain or rather soreness in the hypogastric region, and his pupils were dilated," noted Dr. Addison.
The only abnormal findings at autopsy were in the stomach and supra-renal capsules. Toward the lesser curvature of the stomach, "it was granular, in some parts destroyed, ulcerated; quite superficially there was arborescent injection." The adrenal glands were "exceedingly small and atrophied."
The patient had obviously been ill for some time. Dr. Addison suspected the possibility of "some acrid poison" as the initiating cause of "accidental or essential gastric inflammation" accompanied by the typical supra-renal disease. He described "the extreme and peculiar prostration of the patient's strength, the great feebleness and smallness of the pulse, the anaemiated eye, the absence of any discoverable lesion to account for the patient's condition, and more especially the dingy discoloration of the face, that led before death to a belief that we should on post-mortem examination find disease of the supra-renal capsules."
Re-analysis of the Cases
The 2 cases described above had a severe, chronic, painful condition—one spinal and one gastric—that predated or accompanied the clinical syndrome of adrenal failure. None of the other 9 cases reported by Dr. Addison had chronic pain as a factor in the patients' chronic condition. Tuberculosis and cancer appeared to be the cause of these patients' supra-renal disease because either tuberculosis nodules (tubercles) or carcinomatous infiltrates, respectively, were found in the supra-renal glands.1 In the 2 pain cases, there were no infiltrates, only fibrous tissue. This does not mean that the patients with tuberculosis and cancer were not in pain, but pain did not seem to be the primary cause of their adrenal failure.
The 2 pain cases appear to have a clinical history that is comparable with modern-day observations of severe, intractable pain and adrenal insufficiency.5-12 Severe pain initially stimulates the hypothalamic-pituitary-adrenal (HPA) system to hypersecrete cortisol and other hormones (Figure 5). This results in extremely elevated serum cortisol levels. If the pain remains severe and uncontrolled, the HPA cannot keep up with the stressful demand and cortisol serum levels will drop.
In my clinical practice, patients will report the classic clinical symptoms and pigmented discolorations described by Addison. For example, the 2 images in Figure 6 show women with severe lumbar spine disease and arachnoiditis. Both patients presented with severe constant pain, lethargy, weakness, hypotension, tachycardia, yellowish skin discoloration, and pigmented lesions. One patient has the deep, black freckles described by Addison. Serum cortisol levels in both of these patients were <1.0 mcg/mL.
Interestingly, I am not aware of any reports other than Addison's that describe post-mortem adrenal disease in pain patients. Since constant, severe pain relentlessly stimulates the HPA axis, pathologic changes in adrenal tissue—with both hypertrophy and atrophy as described by Addison—makes logical sense.
Dr. Addison believed that disease of the supra-renals (adrenals) was not a rare occurrence. As a final admonishment he stated: "My experience leads to a belief that the disease is by no means of very rare occurrence, and that were we better acquainted with its symptoms and progress, we should probably succeed in detecting many cases."
Indeed, adrenal insufficiency is proving to be relatively common in chronic pain patients.2,11,12 Fortunately, the full-blown disease associated with total adrenal destruction and death as described by Dr. Addison is probably a rarity today. Thanks to modern technology, adrenal insufficiency is readily detected by blood and saliva assays for cortisol. Today's early access to pain treatment in most ambulatory settings likely relieves enough stress of pain on the HPA axis to prevent adrenal failure and death in all but the rarest cases.
In times past, however, some pain patients who were unable to access treatment likely died of adrenal failure as did Addison's 2 cases. Extremely low or trace cortisol serum levels (<1.0 mcg/mL) have been observed in contemporary pain patients, but these trace levels apparently represent enough cortisol to sustain life for some undetermined time period.2,12 These extremely low levels of serum cortisol do call for urgent cortisol replacement in pain patients because adrenal insufficiency is associated with great debility.
I believe Dr. Addison would be elated that his treatise did what it was intended to do. To this day, it has alerted the profession to the presence of adrenal insufficiency and the need to study and understand it. Adrenal insufficiency caused by severe, intractable pain may be the most common cause of adrenal failure because tuberculosis and carcinoma are relatively well controlled or non-existent. In just the past few years, astute practitioners have begun testing chronic pain patients with hormone profiles. Corticoid replacement in pain patients is in the early stages, and several innovative corticoid replacement techniques are being investigated. We can thank Dr. Addison for not only a "job well done" but one that has had enduring benefits.
Publishing Facts About Dr. Addison's Report
Dr. Addison collected his 11 cases between 1850 and 1854 and they were published in a report, entitled The Constitutional and Local Effects of Disease of the Supra-Renal Capsules, in 1855 by Samuel Highley, a prestigious London publisher. Addison was able to have an artist draw a picture of 8 of the cases to include in the report.
This article on the role of pain in Dr. Addison's adrenal failure patients has been excerpted from a special copyright edition that was privately printed in 1980 for members of "The Classics of Medicine Library," in Birmingham, Alabama.
Film was prepared from an original 1855 edition furnished to the publisher courtesy of the Yale Medical Library. The volume is beautifully bound in top grain genuine cowhide, with end leaves in a marbled design. Edges are gilded, and covers are brass die stamped in 22-karat gold. The beauty of this special edition matches the brilliance of Dr. Addison's pioneering and seminal report.
We thank the publisher for allowing us to reprint these images.
Addison T. The Constitutional and Local Effects of Disease of the Supra-Renal Capsules. London: Samuel Highley; 1855.
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Last updated on: December 8, 2015
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